Bio


Dr. Hsing is a professor of medicine at Stanford University and a co-leader of the Population Sciences Program at Stanford Cancer Institute. A senior fellow for the Center for Innovation in Global Health at Stanford University, Dr. Hsing has conducted population-based epidemiological studies on four continents, including North and South America, Asia, Africa, and Europe. She is a leading expert in the epidemiology and etiology of prostate, hepatobiliary, and thyroid cancers as well as in hormonal carcinogenesis and circadian rhythm. Throughout her 22-year tenure at National Cancer Institute, Dr. Hsing developed extensive expertise in molecular epidemiology, global oncology, cancer prevention, and population-based studies in international settings. She has served on numerous committees and advisory boards, most recently as a member of the Editorial Board of Cancer Epidemiology, Biomarkers & Prevention and as an academic editor of PLOS ONE. She also has served as an adjunct professor in the Department of Epidemiology and the Department of Urology at the George Washington University in Washington, D.C., as well as in the Department of Public Health of Fu Jen Catholic University’s School of Medicine in Taiwan. Dr. Hsing has authored more than 270 peer-reviewed articles, written seven book chapters, and mentored over 50 post-doctoral fellows and scholars.

Dr. Hsing currently serves as PI on the following funded projects:

• A pilot study to assess the feasibility of building a population-based cancer registry in Accra, Ghana;
• A study to assess patterns and trends of liver cancer in the Greater Bay area and in California and to project liver cancer burden in 20 years;
• A pilot study in the Bay area to investigate non-viral factors of liver cancer;
• A pilot study to investigate the clinical utility of ctNDA in post-treatment surveillance of liver cancer in Mongolia;
• A whole genome sequencing study of aggressive thyroid cancer to identify novel prognostic factors;
• A cohort study of 10,000 healthy individuals in Taiwan to investigate social and biochemical determinants of wellness (WELL Taiwan);
• A cohort study of 10,000 healthy individuals in China to investigate social and biochemical determinants of wellness (WELL China);
• A multiethnic cohort study of 550,000 individuals in Singapore to investigate social and biochemical determinants of wellness (WELL Singapore)

She also serves as the Stanford PI of a consortium study of a genome-wide association study (GWAS) of prostate cancer in the African countries of Ghana, Senegal, Nigeria, and South Africa. More recently, her her work involves big data studies using such resources as the National Health Insurance Research Database, SEER-Medicare, and other large administrative claims and medical record databases to identify clinically relevant questions to help inform clinical practice.

Academic Appointments


Administrative Appointments


  • Chair, Pacific Rim Alliances for Population Health (PRAPH) (2017 - Present)
  • Faculty Fellow, Center for Population Health Sciences (2017 - Present)
  • Co-leader, Population Sciences Program, Stanford Cancer Institute (2015 - 2019)
  • Faculty Fellow, Center for Innovation in Global Health, Stanford School of Medicine (2015 - Present)
  • Chair, LDCT Lung Cancer Screening Working Group, Stanford Cancer Institute (2015 - Present)
  • Chair, Liver Cancer Working Group, Stanford Cancer Institute (2014 - Present)
  • Chief Scientific Officer, Cancer Prevention Institute of California (2012 - 2015)

Honors & Awards


  • Member, American Epidemiological Society
  • Member and Chair, Membership Committee, American Epidemiological Society (2016)
  • Member, American Society for Clinical Oncology (ASCO) Cancer Prevention Committee 
  • Chair, American Society of Preventive Oncology (ASPO) Membership Committee
  • Fellow, American College of Epidemiology 
  • Senior Fellow, Center for Innovation in Global Health 
  • NIH, Merit Award
  • NIH, Mentoring Award
  • NIH, Women in Science Monograph
  • NCI, Special Award for leadership as Women Scientist Adivsor
  • NCI, Women Scientist Advisor Achievement Award
  • Member, Editorial Board, Cancer Epidemiology, Biomarkers & Prevention 
  • Academic Editor, PLOS ONE

Boards, Advisory Committees, Professional Organizations


  • Member, Cancer Prevention Committee, American Society of Preventive Oncology (2015 - Present)
  • Member and Chair of Membership Committee, American Society of Preventive Oncology (ASPO) (2012 - Present)
  • Member, American Epidemiological Society (AES) (2003 - Present)
  • Member, African Organization for Research and Training in Cancer (AORTIC) (2000 - Present)
  • Member, American Association for Cancer Research (AACR) (1984 - Present)

Professional Education


  • Post-doctoral Fellowship, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Molecular and Genetic Epidemiology
  • Post-doctoral Fellowship, Johns Hopkins University, Baltimore, MD, Molecular Epidemiology
  • Ph.D., Johns Hopkins University, Baltimore, MD, Epidemiology
  • M.P.H., University of California at Los Angeles, Los Angeles, CA, Biostatistics
  • B.S., Summa Cum Laude, China Medical College, Taichung, Taiwan, Republic of China, Public Health

Current Research and Scholarly Interests


Research Focus
• Epidemiology of prostate, hepatobiliary, and thyroid cancers
• Racial disparities in cancer
• Endogenous hormones/growth factors
• Circadian rhythms
• Chronic inflammation
• Genetic susceptibility
• Cancer prevention and control
• Global oncology and international studies

2020-21 Courses


All Publications


  • Dry eye and sleep quality: a large community-based study in Hangzhou. Sleep Yu, X., Guo, H., Liu, X., Wang, G., Min, Y., Chen, S. S., Han, S. S., Chang, R. T., Zhao, X., Hsing, A., Zhu, S., Yao, K. 2019

    Abstract

    STUDY OBJECTIVES: To investigate the relationship between dry eye and sleep quality in a large community-based Chinese population.METHODS: A total of 3,070 participants aged 18 to 80 were recruited from a community-based study in Hangzhou, China during 2016-2017. Sleep quality was evaluated using the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI), and dry eye was evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. Multivariable linear regression and logistic regression models were used to investigate the associations, adjusting for age, smoking, drinking, season, and other potential confounders.RESULTS: Overall, CPSQI score and sleep dysfunction were significantly associated with mild, moderate, and severe dry eye (ORs for CPSQI score: 1.07, 1.13, 1.14, all p<0.001; for sleep dysfunction: 1.31, 1.73, 1.66, all p<0.05). Furthermore, worse OSDI score was presented in participants with worse CPSQI score or sleep dysfunction (CPSQI score >7) (beta: 0.13, 0.54; all p<0.001). In addition, six of the seven components of CPSQI showed significant associations with dry eye (all p<0.001), except for the component of sleep medication use. Moreover, we observed significant associations of dry eye in all three subscales of OSDI with CPSQI score and sleep dysfunction.CONCLUSION: Our large, community-based study showed a strong association between poor sleep quality and an increased severity of dry eye, suggesting that preventing either one of the discomforts might alleviate the other.

    View details for DOI 10.1093/sleep/zsz160

    View details for PubMedID 31310315

  • Changing Landscape of Liver Cancer in California: A Glimpse Into the Future of Liver Cancer in the United States JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Han, S. S., Kelly, S. P., Li, Y., Yang, B., Nguyen, M., So, S., Rosenberg, P. S., Hsing, A. W. 2019; 111 (6): 550–56
  • Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt". PLoS genetics Gouveia, M. H., Bergen, A. W., Borda, V., Nunes, K., Leal, T. P., Ogwang, M. D., Yeboah, E. D., Mensah, J. E., Kinyera, T., Otim, I., Nabalende, H., Legason, I. D., Mpoloka, S. W., Mokone, G. G., Kerchan, P., Bhatia, K., Reynolds, S. J., Birtwum, R. B., Adjei, A. A., Tettey, Y., Tay, E., Hoover, R., Pfeiffer, R. M., Biggar, R. J., Goedert, J. J., Prokunina-Olsson, L., Dean, M., Yeager, M., Lima-Costa, M. F., Hsing, A. W., Tishkoff, S., Chanock, S. J., Tarazona-Santos, E., Mbulaiteye, S. M. 2019; 15 (3): e1008027

    Abstract

    Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ≥ 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations.

    View details for PubMedID 30849090

  • Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt" PLOS GENETICS Gouveia, M. H., Bergen, A. W., Borda, V., Nunes, K., Leal, T. P., Ogwang, M. D., Yeboah, E. D., Mensah, J. E., Kinyera, T., Otim, I., Nabalende, H., Legason, I. D., Mpoloka, S., Mokone, G., Kerchan, P., Bhatia, K., Reynolds, S. J., Birtwum, R. B., Adjei, A. A., Tettey, Y., Tay, E., Hoover, R., Pfeiffer, R. M., Biggar, R. J., Goedert, J. J., Prokunina-Olsson, L., Dean, M., Yeager, M., Fernanda Lima-Costa, M., Hsing, A. W., Tishkoff, S. A., Chanock, S. J., Tarazona-Santos, E., Mbulaiteye, S. M. 2019; 15 (3)
  • Presentation and survival of multiple myeloma patients in Ghana: a review of 169 cases. Ghana medical journal Acquah, M. E., Hsing, A. W., McGuire, V., Wang, S., Birmann, B., Dei-Adomakoh, Y. 2019; 53 (1): 52–58

    Abstract

    Africans have an increased risk for multiple myeloma (MM) compared to other races. Reports from Africa are few and involve small cohorts, but suggest significant epidemiological and clinical differences from Caucasian patients.This report describes the clinic-pathological features of MM patients in Ghana at diagnosis, and the factors affecting their survival.A retrospective review of 169 MM cases diagnosed in a Ghanaian tertiary hospital from 2002-2016.Median age was 58 years, with 29% ≤50 years. One-third presented >12 months after onset of symptoms, which included bone pain (96%), anaemia (67%), weight loss (55%) and fractures (44%). Myeloma-related tissue impairment included hypercalcaemia (36%), renal impairment (33%), severe anaemia (52%) and osteolytic lesions (76%); 51.3% of patients were diagnosed in ISS Stage III. Median survival was 33 months; 1-year and 5-year overall survival were 51.6% and 15.5%, respectively. Neither the age at diagnosis nor the duration of symptoms prior to diagnosis correlated with prognosis. Median survival improved with early ISS stage, haemoglobin >8g/dL, plasmacytosis <20%, and normal creatinine and calcium levels.Early onset and late stage presentation are common at diagnosis of MM patients in Ghana, but do not affect survival. Studies into genetic associations are recommended.None.

    View details for DOI 10.4314/gmj.v53i1.8

    View details for PubMedID 31138944

    View details for PubMedCentralID PMC6527826

  • Association of circulating inflammation proteins and gallstone disease JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Liu, Z., Kemp, T. J., Gao, Y., Corbel, A., McGee, E. E., Wang, B., Shen, M., Rashid, A., Hsing, A. W., Hildesheim, A., Pfeiffer, R. M., Pinto, L. A., Koshiol, J. 2018; 33 (11): 1920–24

    Abstract

    Inflammation plays a role in the development of both gallstones and gallbladder cancer; however, few studies have investigated the association of circulating inflammation proteins with risk of gallstones.This study measured 13 cytokines (including 10 interleukins [ILs]) that have been associated with cancer in serum samples collected from 150 gallstone patients and 149 population-based controls from Shanghai, China, in 1997-2001. This study estimated the associations of each cytokine, categorized into quartiles and coded as a trend, with risk of gallstones using logistic regression models adjusted for potential confounders.Higher levels of IL-6, IL-10, IL-12 (p70), and IL-13 were associated with increased risk of gallstones (i.e. Ptrend  < 0.003, Bonferroni corrected), with odds ratios (ORs) that ranged from ORhighest quartile [Q4] versus lowest quartile [Q1]  = 3.2 (95% confidence interval: 1.4, 7.5) for IL-13 to ORQ4 versus Q1  = 5.7 (95% confidence interval: 2.5, 13.5) for IL-12 (p70). In a regression model including all four ILs, only IL-12 retained statistical significance (P < 0.05).This study found four circulating ILs that were associated with gallstones. Future studies are needed to validate the findings and evaluate the common pathway or mechanism in the development of gallbladder diseases associated with these cytokine signatures.

    View details for PubMedID 29671891

  • Racial/ethnic- and county-specific prevalence of chronic hepatitis B and its burden in California Hepatology, Medicine and Policy Toy, M., Wei, B., Virdi, T. S., Le, A., Trinh, H., Li, J., Zhang, J., Hsing, A. W., So, S. K., Nguyen, M. H. 2018; 3 (6)
  • Patient and primary care provider attitudes and adherence towards lung cancer screening at an academic medical center. Preventive medicine reports Duong, D. K., Shariff-Marco, S., Cheng, I., Naemi, H., Moy, L. M., Haile, R., Singh, B., Leung, A., Hsing, A., Nair, V. S. 2017; 6: 17-22

    Abstract

    Low dose CT (LDCT) for lung cancer screening is an evidence-based, guideline recommended, and Medicare approved test but uptake requires further study. We therefore conducted patient and provider surveys to elucidate factors associated with utilization. Patients referred for LDCT at an academic medical center were questioned about their attitudes, knowledge, and beliefs on lung cancer screening. Adherent patients were defined as those who met screening eligibility criteria and completed a LDCT. Referring primary care providers within this same medical system were surveyed in parallel about their practice patterns, attitudes, knowledge and beliefs about screening. Eighty patients responded (36%), 48 of whom were adherent. Among responders, non-Hispanic patients (p = 0.04) were more adherent. Adherent respondents believed that CT technology is accurate and early detection is useful, and they trusted their providers. A majority of non-adherent patients (79%) self-reported an intention to obtain a LDCT in the future. Of 36 of 87 (41%) responding providers, only 31% knew the correct lung cancer screening eligibility criteria, which led to a 37% inappropriate referral rate from 2013 to 2015. Yet, 75% had initiated lung cancer screening discussions, 64% thought screening was at least moderately effective, and 82% were interested in learning more of the 33 providers responding to these questions. Overall, patients were motivated and providers engaged to screen for lung cancer by LDCT. Non-adherent patient "procrastinators" were motivated to undergo screening in the future. Additional follow through on non-adherence may enhance screening uptake, and raising awareness for screening eligibility through provider education may reduce inappropriate referrals.

    View details for DOI 10.1016/j.pmedr.2017.01.012

    View details for PubMedID 28210538

    View details for PubMedCentralID PMC5304233

  • Salmonella enterica serovar Typhi and gallbladder cancer: a case-control study and meta-analysis. Cancer medicine Koshiol, J., Wozniak, A., Cook, P., Adaniel, C., Acevedo, J., Azócar, L., Hsing, A. W., Roa, J. C., Pasetti, M. F., Miquel, J. F., Levine, M. M., Ferreccio, C. 2016

    Abstract

    In Chile, where gallbladder cancer (GBC) rates are high and typhoid fever was endemic until the 1990s, we evaluated the association between Salmonella enterica serovar Typhi (S. Typhi) antibodies and GBC. We tested 39 GBC cases, 40 gallstone controls, and 39 population-based controls for S. Typhi Vi antibodies and performed culture and quantitative polymerase chain reaction for the subset with bile, gallstone, tissue, and stool samples available. We calculated gender and education-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association with GBC. We also conducted a meta-analysis of >1000 GBC cases by combining our results with previous studies. GBC cases were more likely to have high Vi antibody titer levels than combined controls (OR: 4.0, 95% CI: 0.9-18.3), although S. Typhi was not recovered from bile, gallstone, tissue, or stool samples. In our meta-analysis, the summary relative risk was 4.6 (95% CI: 3.1-6.8, Pheterogeneity =0.6) for anti-Vi and 5.0 (95% CI: 2.7-9.3, Pheterogeneity  = 0.2) for bile or stool culture. Our results are consistent with the meta-analysis. Despite differences in study methods (e.g., S. Typhi detection assay), most studies found a positive association between S. Typhi and GBC. However, the mechanism underlying this association requires further investigation.

    View details for DOI 10.1002/cam4.915

    View details for PubMedID 27726295

    View details for PubMedCentralID PMC5119987

  • Reduction of chronic hepatitis B-related hepatocellular carcinoma with anti-viral therapy, including low risk patients. Alimentary pharmacology & therapeutics LIN, D., Yang, H., Nguyen, N., Hoang, J., Kim, Y., Vu, V., Le, A., Chaung, K., Nguyen, V., Trinh, H., Li, J., Zhang, J., Hsing, A., Chen, C., Nguyen, M. H. 2016; 44 (8): 846-855

    Abstract

    Anti-viral therapy in chronic hepatitis B (CHB) is associated with a reduced risk of hepatocellular carcinoma (HCC) primary described in patients with cirrhosis.To examine the effects of treatment on HCC incidence in CHB with and without cirrhosis, after adjustment for background risks.A total of 2255 CHB patients from a US cohort (973 received anti-viral therapy) and 3653 patients from the community-based Taiwanese REVEAL-HBV study, none of whom received treatment. We used Cox proportional hazard models to calculate the risk of developing HCC after adjustment with the previously validated REACH-B risk score.We found 273 incident cases of HCC. After adjustment, therapy lowered the risk of HCC development in the US treated cohort when compared to the US untreated cohort (HR 0.31; 95% CI: 0.15-0.66; P = 0.002). HCC risk reduction was also confirmed when compared to the REVEAL cohort (HR 0.22; 95% CI: 0.12-0.40; P < 0.001). Each REACH-B point was associated with a 53% increased risk of HCC (HR 1.53; 95% CI 1.46-1.59; P < 0.001). We found a significant statistical reduction in HCC incidence with therapy regardless of gender, age, cirrhosis status, HBeAg serology, alanine aminotransferase level, REACH-B score or treatment medication. Therapy was beneficial to those with mildly- to moderately elevated HBV DNA levels (>2000 IU/mL) and of even greater benefit to those with levels >200 000 IU/mL.After adjustment for background risk, anti-viral therapy was associated with a significant reduction in HCC incidence in both community and real-life clinical cohorts, including in those patients previously thought to be at low risk.

    View details for DOI 10.1111/apt.13774

    View details for PubMedID 27549411

  • Lipopolysaccharide-pathway proteins are associated with gallbladder cancer among adults in Shanghai, China with mediation by systemic inflammation. Annals of epidemiology Van Dyke, A. L., Kemp, T. J., Corbel, A. F., Zhu, B., Gao, Y., Wang, B., Rashid, A., Shen, M., Hildesheim, A., Hsing, A. W., Pinto, L. A., Koshiol, J. 2016; 26 (10): 704-709

    Abstract

    We examined inflammation as a mediator of associations between bacterial infection markers and gallbladder cancer (GBC).Bacterial response proteins (lipopolysaccharide [LPS], soluble cluster of differentiation 14 [sCD14], and LPS-binding protein [LBP]) were measured in 40 GBC cases and 126 gallstone controls with data on 63 serum inflammation markers. The relationships of LPS, LBP, and sCD14 with GBC were examined by logistic regression, which also was used to evaluate whether these associations are influenced by systemic inflammation as measured by a combinatorial inflammation score.The third versus the first tertiles of sCD14 and of LBP were associated with an increased GBC risk (odds ratio [95% confidence interval]: 5.41 [2.00-16.75] for sCD14, and 6.49 [2.24-23.79] for LBP). sCD14 and LBP were strongly associated with inflammation score (above vs. below the median), which itself was associated with a more than 21-fold increased risk of GBC for the third versus first tertiles. Associations between GBC and sCD14 and LBP were markedly attenuated when the inflammation score was included in the model. While LPS was not associated with GBC or inflammation, only 35% of cases and 22% of controls had detectable levels.These findings suggest that these LPS-pathway proteins are associated with GBC via inflammation-related pathways.

    View details for DOI 10.1016/j.annepidem.2016.08.009

    View details for PubMedID 27793274

    View details for PubMedCentralID PMC5123694

  • Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial CANCER Price, D. K., Chau, C. H., Till, C., Goodman, P. J., Leach, R. J., Johnson-Pais, T. L., Hsing, A. W., Hoque, A., Parnes, H. L., Schenk, J. M., Tangen, C. M., Thompson, I. M., Reichardt, J. K., Figg, W. D. 2016; 122 (15): 2332-2340

    Abstract

    Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment.A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations.There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend < .05) were significantly associated with both circulating hormone levels and prostate cancer risk.Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016;122:2332-2340. © 2016 American Cancer Society.

    View details for DOI 10.1002/cncr.30071

    View details for PubMedID 27164191

  • Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. Journal of the National Cancer Institute Han, Y., Rand, K. A., Hazelett, D. J., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Stanford, J. L., Zheng, W., Schumacher, F. R., Berndt, S. I., Wang, Z., Xu, J., Rohland, N., Reich, D., Tandon, A., Pasaniuc, B., Allen, A., Quinque, D., Mallick, S., Notani, D., Rosenfeld, M. G., Jayani, R. S., Kolb, S., Gapstur, S. M., Stevens, V. L., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., John, E. M., Murphy, A. B., Signorello, L. B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Witte, J. S., Casey, G., Lubwama, A., Pooler, L. C., Sheng, X., Coetzee, G. A., Cook, M. B., Chanock, S. J., Stram, D. O., Watya, S., Blot, W. J., Conti, D. V., Henderson, B. E., Haiman, C. A. 2016; 108 (7)

    Abstract

    The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

    View details for DOI 10.1093/jnci/djv431

    View details for PubMedID 26823525

  • Association of inflammatory and other immune markers with gallbladder cancer: Results from two independent case-control studies. Cytokine Koshiol, J., Castro, F., Kemp, T. J., Gao, Y., Roa, J. C., Wang, B., Nogueira, L., Araya, J. C., Shen, M., Rashid, A., Hsing, A. W., Hildesheim, A., Ferreccio, C., Pfeiffer, R. M., Pinto, L. A. 2016; 83: 217-225

    Abstract

    Most gallbladder cancer (GBC) cases arise in the context of gallstones, which cause inflammation, but few gallstone patients develop GBC. We explored inflammation/immune-related markers measured in bile and serum in GBC cases compared to gallstone patients to better understand how inflammatory patterns in these two conditions differ. We measured 65 immune-related markers in serum and bile from 41 GBC cases and 127 gallstone patients from Shanghai, China, and calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GBC versus gallstones. We then focused on the markers that were significantly elevated in bile and serum to replicate the findings in serum from 35 GBC cases and 31 gallstone controls from Chile. Comparing the highest versus lowest quantile, 15 markers (23%) were elevated in both serum and bile from GBC versus gallstone patients in the Shanghai study (p<0.05). The strongest OR was for CXCL8 (interleukin-8) in serum (96.8, 95% CI: 11.9-790.2). Of these 15 markers, 6 were also significantly elevated in serum from Chile (CCL20, C-reactive protein, CXCL8, CXCL10, resistin, serum amyloid A). Pooled ORs from Shanghai and Chile for these 6 markers ranged from 7.2 (95% CI: 2.8-18.4) for CXCL10 to 58.2 (95% CI: 12.4-273.0) for CXCL8. GBC is associated with inflammation above and beyond that generated by gallstones alone. This local inflammatory process is reflected systemically. Future longitudinal studies are needed to identify the key players in cancer development, which may guide translational efforts to identify individuals at high risk of developing GBC.

    View details for DOI 10.1016/j.cyto.2016.05.003

    View details for PubMedID 27173614

  • Association of inflammatory and other immune markers with gallbladder cancer: Results from two independent case-control studies CYTOKINE Koshiol, J., Castro, F., Kemp, T. J., Gao, Y., Carlos Roa, J., Wang, B., Nogueira, L., Carlos Araya, J., Shen, M., Rashid, A., Hsing, A. W., Hildesheim, A., Ferreccio, C., Pfeiffer, R. M., Pinto, L. A. 2016; 83: 217-225
  • Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation NATURE COMMUNICATIONS Gusev, A., Shi, H., Kichaev, G., Pomerantz, M., Li, F., Long, H. W., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Zheng, W., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., John, E. M., Murphy, A. B., Signorello, L. B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Witte, J. S., Casey, G., Kaggwa, S., Cook, M. B., Stram, D. O., Blot, W. J., Eeles, R. A., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Southey, M. C., FitzGerald, L. M., Gronberg, H., Wiklund, F., Aly, M., Henderson, B. E., Schleutker, J., Wahlfors, T., Tammela, T. L., Nordestgaard, B. G., Key, T. J., Travis, R. C., Neal, D. E., Donovan, J. L., Hamdy, F. C., Pharoah, P., Pashayan, N., Khaw, K., Stanford, J. L., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Maier, C., Vogel, W., Luedeke, M., Herkommer, K., Kibel, A. S., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Cannon-Albright, L., Teerlink, C., Brenner, H., Dieffenbach, A. K., Arndt, V., Park, J. Y., Sellers, T. A., Lin, H., Slavov, C., Kaneva, R., Mitev, V., Batra, J., Spurdle, A., Clements, J. A., Teixeira, M. R., Pandha, H., Michael, A., Paulo, P., Maia, S., Kierzek, A., Conti, D. V., Albanes, D., Berg, C., Berndt, S. I., Campa, D., Crawford, E. D., Diver, W. R., Gapstur, S. M., Gaziano, J. M., Giovannucci, E., Hoover, R., Hunter, D. J., Johansson, M., Kraft, P., Le Marchand, L., Lindstrom, S., Navarro, C., Overvad, K., Riboli, E., Siddiq, A., Stevens, V. L., Trichopoulos, D., Vineis, P., Yeager, M., Trynka, G., Raychaudhuri, S., Schumacher, F. R., Price, A. L., Freedman, M. L., Haiman, C. A., Pasaniuc, B., Cook, M., Guy, M., Govindasami, K., Leongamornlert, D., Sawyer, E. J., Wilkinson, R., Saunders, E. J., Tymrakiewicz, M., Dadaev, T., Morgan, A., Fisher, C., Hazel, S., Livni, N., Lophatananon, A., Pedersen, J., Hopper, J. L., Adolfson, J., Stattin, P., Johansson, J., Cavalli-Bjoerkman, C., Karlsson, A., Broms, M., Auvinen, A., Kujala, P., Maeaettaenen, L., Murtola, T., Taari, K., Weischer, M., Nielsen, S. F., Klarskov, P., Roder, A., Iversen, P., Wallinder, H., Gustafsson, S., Cox, A., Brown, P., George, A., Marsden, G., Lane, A., Davis, M., Zheng, W., Signorello, L. B., Blot, W. J., Tillmans, L., Riska, S., Wang, L., Rinckleb, A., Lubiski, J., Stegmaier, C., Pow-Sang, J., Park, H., Radlein, S., Rincon, M., Haley, J., Zachariah, B., Kachakova, D., Popov, E., Mitkova, A., Vlahova, A., Dikov, T., Christova, S., Heathcote, P., Wood, G., Malone, G., Saunders, P., Eckert, A., Yeadon, T., Kerr, K., Collins, A., Turner, M., Srinivasan, S., Kedda, M., Alexander, K., Omara, T., Wu, H., Henrique, R., Pinto, P., Santos, J., Barros-Silva, J. 2016; 7

    Abstract

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

    View details for DOI 10.1038/ncomms10979

    View details for PubMedID 27052111

  • Serum androgens and prostate cancer risk: results from the placebo arm of the Prostate Cancer Prevention Trial CANCER CAUSES & CONTROL Schenk, J. M., Till, C., Hsing, A. W., Stanczyk, F. Z., Gong, Z., Neuhouser, M. L., Reichardt, J. K., Hoque, A. M., Figg, W. D., Goodman, P. J., Tangen, C. M., Thompson, I. M. 2016; 27 (2): 175-182

    Abstract

    Compelling and long-standing data suggest that androgens play an important role in the development of both normal prostate epithelium and prostate cancer. Although testosterone administration can induce prostate cancer (PCA) in laboratory animals, serum-based epidemiologic studies examining androgens in humans have not consistently supported a role for androgens in prostate carcinogenesis. We examined whether pre-diagnostic serum androgens were associated with PCA risk in the placebo arm of the Prostate Cancer Prevention Trial.In this nested case-control study, cases (n = 1,032) were primarily local-stage, biopsy-detected cancers, and controls (n = 1,025) were biopsy-confirmed to be PCA-free. Pre-diagnostic serum androgens (total testosterone, 3α-androstanediol glucuronide, free testosterone), estrogen-to-testosterone ratio, and sex hormone-binding globulin (SHBG) concentrations were measured in pooled (baseline and year 3) blood samples.We found no significant associations between serum androgens, estrogen-to-testosterone ratios, or SHBG and risk of total, low (Gleason <7) or high-grade (Gleason 7-10) PCA.Much remains to be learned about the role of androgens in prostate carcinogenesis. Further research is needed to evaluate the role of androgens, timing of exposure, genetic modulators of androgen metabolism, or environmental exposures that may affect androgen influence on prostate carcinogenesis.

    View details for DOI 10.1007/s10552-015-0695-0

    View details for PubMedID 26589415

  • Korean National Health Insurance Database Reply JAMA INTERNAL MEDICINE Hsing, A., Ioannidis, J. P. 2016; 176 (1): 138-139

    View details for PubMedID 26747668

  • Sleep Duration and Cancer in the NIH-AARP Diet and Health Study Cohort. PloS one Gu, F., Xiao, Q., Chu, L. W., Yu, K., Matthews, C. E., Hsing, A. W., Caporaso, N. E. 2016; 11 (9)

    Abstract

    Very few studies have examined sleep duration in relation to cancer incidence with the exception of breast cancer.We assessed the associations between sleep duration and incidences of total and 18 site-specific cancers in the NIH-AARP Health and Diet Study cohort, with 173,327 men and 123,858 women aged 51-72 years at baseline. Self-reported sleep duration categories were assessed via questionnaire. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), using 7-8 hours/night as the reference.We observed a significantly increased risk of stomach cancer among male short sleepers (multivariable HR5-6 vs. 7-8 hours = 1.29; 95%CI: 1.05, 1.59; Ptrend = 0.03). We also observed suggestive associations in either short or long sleepers, which did not reach overall significance (Ptrend >0.05), including increased risks in male short sleepers for cancers of head and neck (HR<5vs.7-8 hours = 1.39; 95%CI:1.00-1.95), bladder (HR5-6vs.7-8 hours = 1.10; 95%CI:1.00-1.20), thyroid (HR<5 vs. 7-8 hours = 2.30; 95%CI:1.06, 5.02), Non-Hodgkin Lymphoma (NHL) (HR5-6vs.7-8 hours = 1.17; 95%CI:1.02-1.33), and myeloma (HR<5vs.7-8 hours = 2.06; 95%CI:1.20-3.51). In women, the suggestive associations include a decreased total cancer risk (HR<5vs.7-8 hours = 0.9; 95%CI:0.83-0.99) and breast cancer risk (HR<5vs.7-8 hours = 0.84; 95%CI:0.71-0.98) among short sleepers. A decreased ovarian cancer risk (HR≥ 9 vs. 7-8 hours = 0.50; 95%CI:0.26-0.97) and an increased NHL risk (HR≥ 9 vs. 7-8 hours = 1.45; 95%CI:1.00-2.11) were observed among long sleepers.In an older population, we observed an increased stomach cancer risk in male short sleepers and suggestive associations with short or long sleep duration for many cancer risks in both genders.

    View details for DOI 10.1371/journal.pone.0161561

    View details for PubMedID 27611440

  • Del1 Knockout Mice Developed More Severe Osteoarthritis Associated with Increased Susceptibility of Chondrocytes to Apoptosis. PloS one Wang, Z., Tran, M. C., Bhatia, N. J., Hsing, A. W., Chen, C., LaRussa, M. F., Fattakhov, E., Rashidi, V., Jang, K. Y., Choo, K. J., Nie, X., Mathy, J. A., Longaker, M. T., Dauskardt, R. H., Helms, J. A., Yang, G. P. 2016; 11 (8)

    Abstract

    We identified significant expression of the matricellular protein, DEL1, in hypertrophic and mature cartilage during development. We hypothesized that this tissue-specific expression indicated a biological role for DEL1 in cartilage biology.Del1 KO and WT mice had cartilage thickness evaluated by histomorphometry. Additional mice underwent medial meniscectomy to induce osteoarthritis, and were assayed at 1 week for apoptosis by TUNEL staining and at 8 weeks for histology and OA scoring. In vitro proliferation and apoptosis assays were performed on primary chondrocytes.Deletion of the Del1 gene led to decreased amounts of cartilage in the ears and knee joints in mice with otherwise normal skeletal morphology. Destabilization of the knee led to more severe OA compared to controls. In vitro, DEL1 blocked apoptosis in chondrocytes.Osteoarthritis is among the most prevalent diseases worldwide and increasing in incidence as our population ages. Initiation begins with an injury resulting in the release of inflammatory mediators. Excessive production of inflammatory mediators results in apoptosis of chondrocytes. Because of the limited ability of chondrocytes to regenerate, articular cartilage deteriorates leading to the clinical symptoms including severe pain and decreased mobility. No treatments effectively block the progression of OA. We propose that direct modulation of chondrocyte apoptosis is a key variable in the etiology of OA, and therapies aimed at preventing this important step represent a new class of regenerative medicine targets.

    View details for DOI 10.1371/journal.pone.0160684

    View details for PubMedID 27505251

  • Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. Human molecular genetics Han, Y., Hazelett, D. J., Wiklund, F., Schumacher, F. R., Stram, D. O., Berndt, S. I., Wang, Z., Rand, K. A., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Xu, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Takahashi, A., Kubo, M., Stanford, J. L., Kolb, S., Gapstur, S. M., Diver, W. R., Stevens, V. L., Strom, S. S., Pettaway, C. A., Al Olama, A. A., Kote-Jarai, Z., Eeles, R. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., Isaacs, W. B., Chen, C., Lindstrom, S., Le Marchand, L., Giovannucci, E. L., Pomerantz, M., Long, H., Li, F., Ma, J., Stampfer, M., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Blot, W. J., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Witte, J. S., Casey, G., Riboli, E., Li, Q., Freedman, M. L., Hunter, D. J., Gronberg, H., Cook, M. B., Nakagawa, H., Kraft, P., Chanock, S. J., Easton, D. F., Henderson, B. E., Coetzee, G. A., Conti, D. V., Haiman, C. A. 2015; 24 (19): 5603-5618

    Abstract

    Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

    View details for DOI 10.1093/hmg/ddv269

    View details for PubMedID 26162851

  • Nationwide Population Science: Lessons From the Taiwan National Health Insurance Research Database. JAMA internal medicine Hsing, A. W., Ioannidis, J. P. 2015; 175 (9): 1527-1529

    View details for DOI 10.1001/jamainternmed.2015.3540

    View details for PubMedID 26192815

  • Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults PLOS ONE Chen, F., He, J., Zhang, J., Chen, G. K., Thomas, V., Ambrosone, C. B., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Cai, Q., Carpten, J., Casey, G., Chanock, S. J., Cheng, I., Chu, L., Deming, S. L., Driver, W. R., Goodman, P., Hayes, R. B., Hennis, A. J., Hsing, A. W., Hu, J. J., Ingles, S. A., John, E. M., Kittles, R. A., Kolb, S., Leske, M. C., Millikan, R. C., Monroe, K. R., Murphy, A., Nemesure, B., Neslund-Dudas, C., Nyante, S., Ostrander, E. A., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schumacher, F., Stanford, J. L., Signorello, L. B., Strom, S. S., Stevens, V., Van Den Berg, D., Wang, Z., Witte, J. S., Wu, S., Yamamura, Y., Zheng, W., Ziegler, R. G., Stram, A. H., Kolonel, L. N., Le Marchand, L., Henderson, B. E., Haiman, C. A., Stram, D. O. 2015; 10 (6)

    Abstract

    Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

    View details for DOI 10.1371/journal.pone.0131106

    View details for Web of Science ID 000358151300033

    View details for PubMedCentralID PMC4488332

  • Epidemiology of GIST in the Era of Histology Codes--Letter. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Lin, A., Hsing, A. W., Ravdin, P. M. 2015; 24 (6): 998-?

    View details for DOI 10.1158/1055-9965.EPI-15-0001

    View details for PubMedID 26033756

  • Preanalytical considerations in the design of clinical trials and epidemiological studies. Clinical chemistry Kellogg, M. D., Ellervik, C., Morrow, D., Hsing, A., Stein, E., Sethi, A. A. 2015; 61 (6): 797-803

    View details for DOI 10.1373/clinchem.2014.226118

    View details for PubMedID 25901083

  • Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies LANCET Gapstur, S. M., Patel, A. V., Banks, E., Dal Maso, L., Talamini, R., Chetrit, A., Hirsh-Yechezkel, G., Lubin, F., Sadetzki, S., Beral, V., Bull, D., Cairns, B., Crossley, B., Gaitskell, K., Goodill, A., Green, J., Hermon, C., Key, T., Moser, K., Reeves, G., Sitas, F., Collins, R., Peto, R., Gonzalez, C. A., Lee, N., Marchbanks, P., Ory, H. W., Peterson, H. B., Wingo, P. A., Martin, N., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., Goodman, M. T., Lidegaard, O., Kjaer, S. K., Morch, L. S., Kjaer, S. K., Tjonneland, A., Byers, T., Rohan, T., Mosgaard, B., Vessey, M., Yeates, D., Freudenheim, J. L., TITUS, L. J., Chang-Claude, J., Kaaks, R., Anderson, K. E., Lazovich, D., Robien, K., Hampton, J., Newcomb, P. A., Rossing, M. A., Thomas, D. B., Weiss, N. S., Lokkegaard, E., Riboli, E., Clavel-Chapelon, F., Cramer, D., Hankinson, S. E., Tamimi, R. M., Tworoger, S. S., Franceschi, S., La Vecchia, C., Negri, E., Adami, H. O., Magnusson, C., Riman, T., Weiderpass, E., Wolk, A., Schouten, L. J., van den Brandt, P. A., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Palli, D., Black, A., Brinton, L. A., Freedman, D. M., Hartge, P., Hsing, A. W., Jnr, J. V., Lissowska, J., HOOVER, R. N., Schairer, C., Babb, C., Urban, M., Graff-Iversen, S., Selmer, R., Bain, C. J., Green, A. C., Purdie, D. M., Siskind, V., Webb, P. M., Moysich, K., McCann, S. E., Hannaford, P., Kay, C., Binns, C. W., Lee, A. H., Zhang, M., Ness, R. B., Nasca, P., Coogan, P. F., Palmer, J. R., Rosenberg, L., Whittemore, A., Katsouyanni, K., Trichopoulou, A., Trichopoulos, D., Tzonou, A., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Lurie, G., Carney, M. E., Wilkens, L. R., Hartman, L., Manjer, J., Olsson, H., Kumle, M., Grisso, J. A., Morgan, M., Wheeler, J. E., Edwards, R. P., Kelley, J. L., Modugno, F., Onland-Moret, N. C., Peeters, P. H., Casagrande, J., Pike, M. C., Wu, A. H., Canfell, K., Miller, A. B., Gram, I. T., Lund, E., McGowan, L., Shu, X. O., Zheng, W., Farley, T. M., Holck, S., MEIRIK, O., Risch, H. A. 2015; 385 (9980): 1835-1842

    Abstract

    Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk.Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use.During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31-1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29-1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40-1·66; p<0·0001) and endometrioid (1·42, 1·20-1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07-1·46, p=0·005).The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users.Medical Research Council, Cancer Research UK.

    View details for DOI 10.1016/S0140-6736(14)61687-1

    View details for Web of Science ID 000354184500027

    View details for PubMedID 25684585

    View details for PubMedCentralID PMC4427760

  • Finasteride Concentrations and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial PLOS ONE Chau, C. H., Price, D. K., Till, C., Goodman, P. J., Chen, X., Leach, R. J., Johnson-Pais, T. L., Hsing, A. W., Hoque, A., Tangen, C. M., Chu, L., Parnes, H. L., Schenk, J. M., Reichardt, J. K., Thompson, I. M., Figg, W. D. 2015; 10 (5)

    Abstract

    In the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer by 25%, even though high-grade prostate cancer was more common in the finasteride group. However, it remains to be determined whether finasteride concentrations may affect prostate cancer risk. In this study, we examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations.Data for this nested case-control study are from the PCPT. Cases were drawn from men with biopsy-proven prostate cancer and matched controls. Finasteride concentrations were measured using a liquid chromatography-mass spectrometry validated assay. The association of serum finasteride concentrations with prostate cancer risk was determined by logistic regression. We also examine whether polymorphisms in the enzyme target and metabolism genes of finasteride are related to drug concentrations using linear regression.Among men with detectable finasteride concentrations, there was no association between finasteride concentrations and prostate cancer risk, low-grade or high-grade, when finasteride concentration was analyzed as a continuous variable or categorized by cutoff points. Since there was no concentration-dependent effect on prostate cancer, any exposure to finasteride intake may reduce prostate cancer risk. Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway.ClinicalTrials.gov NCT00288106.

    View details for DOI 10.1371/journal.pone.0126672

    View details for Web of Science ID 000356768100139

    View details for PubMedCentralID PMC4425512

  • Application of multiplex arrays for cytokine and chemokine profiling of bile CYTOKINE Kemp, T. J., Castro, F. A., Gao, Y., Hildesheim, A., Nogueira, L., Wang, B., Sun, L., Shelton, G., Pfeiffer, R. M., Hsing, A. W., Pinto, L. A., Koshiol, J. 2015; 73 (1): 84-90

    Abstract

    Gallbladder disease is highly related to inflammation, but the inflammatory processes are not well understood. Bile provides a direct substrate in assessing the local inflammatory response that develops in the gallbladder. To assess the reproducibility of measuring inflammatory markers in bile, we designed a methods study of 69 multiplexed immune-related markers measured in bile obtained from gallstone patients.To evaluate assay performance, a total of 18 bile samples were tested twice within the same plate for each analyte, and the 18 bile samples were tested on two different days for each analyte. We used the following performance parameters: detectability, coefficient of variation (CV), intraclass correlation coefficient (ICC), and percent agreement (concordance among replicate measures above and below detection limit). Furthermore, we examined the association of analyte levels with gallstone characteristics such as type, numbers, and size.All but 3 analytes (Stem Cell Factor, SCF; Thrombopoietin, TPO; sIL-1RI) were detectable in bile. 52 of 69 (75.4%) analytes had detectable levels for at least 50% of the subjects tested. The within-plate CVs were ⩽25% for 53 of 66 (80.3%) detectable analytes, and across-plate CVs were ⩽25% for 32 of 66 (48.5%) detectable analytes. Moreover, 64 of 66 (97.0%) analytes had ICC values of at least 0.8. Lastly, the percent agreement was high between replicates for all of the analytes (median; within plate, 97.2%; across plate, 97.2%). In exploratory analyses, we assessed analyte levels by gallstone characteristics and found that levels for several analytes decreased with increasing size of the largest gallstone per patient.Our data suggest that multiplex assays can be used to reliably measure cytokines and chemokines in bile. In addition, gallstone size was inversely related to the levels of select analytes, which may aid in identifying critical pathways and mechanisms associated with the pathogenesis of gallbladder diseases.

    View details for DOI 10.1016/j.cyto.2015.01.033

    View details for Web of Science ID 000353078500013

    View details for PubMedCentralID PMC4382212

  • Application of multiplex arrays for cytokine and chemokine profiling of bile. Cytokine Kemp, T. J., Castro, F. A., Gao, Y., Hildesheim, A., Nogueira, L., Wang, B., Sun, L., Shelton, G., Pfeiffer, R. M., Hsing, A. W., Pinto, L. A., Koshiol, J. 2015; 73 (1): 84-90

    Abstract

    Gallbladder disease is highly related to inflammation, but the inflammatory processes are not well understood. Bile provides a direct substrate in assessing the local inflammatory response that develops in the gallbladder. To assess the reproducibility of measuring inflammatory markers in bile, we designed a methods study of 69 multiplexed immune-related markers measured in bile obtained from gallstone patients.To evaluate assay performance, a total of 18 bile samples were tested twice within the same plate for each analyte, and the 18 bile samples were tested on two different days for each analyte. We used the following performance parameters: detectability, coefficient of variation (CV), intraclass correlation coefficient (ICC), and percent agreement (concordance among replicate measures above and below detection limit). Furthermore, we examined the association of analyte levels with gallstone characteristics such as type, numbers, and size.All but 3 analytes (Stem Cell Factor, SCF; Thrombopoietin, TPO; sIL-1RI) were detectable in bile. 52 of 69 (75.4%) analytes had detectable levels for at least 50% of the subjects tested. The within-plate CVs were ⩽25% for 53 of 66 (80.3%) detectable analytes, and across-plate CVs were ⩽25% for 32 of 66 (48.5%) detectable analytes. Moreover, 64 of 66 (97.0%) analytes had ICC values of at least 0.8. Lastly, the percent agreement was high between replicates for all of the analytes (median; within plate, 97.2%; across plate, 97.2%). In exploratory analyses, we assessed analyte levels by gallstone characteristics and found that levels for several analytes decreased with increasing size of the largest gallstone per patient.Our data suggest that multiplex assays can be used to reliably measure cytokines and chemokines in bile. In addition, gallstone size was inversely related to the levels of select analytes, which may aid in identifying critical pathways and mechanisms associated with the pathogenesis of gallbladder diseases.

    View details for DOI 10.1016/j.cyto.2015.01.033

    View details for PubMedID 25743242

    View details for PubMedCentralID PMC4382212

  • Generalizability of established prostate cancer risk variants in men of African ancestry INTERNATIONAL JOURNAL OF CANCER Han, Y., Signorello, L. B., Strom, S. S., Kittles, R. A., Rybicki, B. A., Stanford, J. L., Goodman, P. J., Berndt, S. I., Carpten, J., Casey, G., Chu, L., Conti, D. V., Rand, K. A., Diver, W. R., Hennis, A. J., John, E. M., Kibel, A. S., Klein, E. A., Kolb, S., Le Marchand, L., Leske, M. C., Murphy, A. B., Neslund-Dudas, C., Park, J. Y., Pettaway, C., Rebbeck, T. R., Gapstur, S. M., Zheng, S. L., Wu, S., Witte, J. S., Xu, J., Isaacs, W., Ingles, S. A., Hsing, A., Easton, D. F., Eeles, R. A., Schumacher, F. R., Chanock, S., Nemesure, B., Blot, W. J., Stram, D. O., Henderson, B. E., Haiman, C. A. 2015; 136 (5): 1210-1217

    Abstract

    Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

    View details for DOI 10.1002/ijc.29066

    View details for Web of Science ID 000346350500046

    View details for PubMedCentralID PMC4268262

  • Effect of Finasteride on Serum Androstenedione and Risk of Prostate Cancer Within the Prostate Cancer Prevention Trial: Differential Effect on High- and Low-grade Disease UROLOGY Hoque, A., Yao, S., Till, C., Kristal, A. R., Goodman, P. J., Hsing, A. W., Tangen, C. M., Platz, E. A., Stanczyk, F. Z., Reichardt, J. K., VanBokhoven, A., Neuhouser, M. L., Santella, R. M., Figg, W. D., Price, D. K., Parnes, H. L., Lippman, S. M., Ambrosone, C. B., Thompson, I. M. 2015; 85 (3): 616-620

    Abstract

    To evaluate the effect of finasteride on serum androst-4-ene-3,17-dione (androstenedione) and its association with prostate cancer risk among subjects who participated in the Prostate Cancer Prevention Trial.We analyzed serum androstenedione levels in 317 prostate cancer cases and 353 controls, nested in the Prostate Cancer Prevention Trial, a randomized placebo-controlled trial that found finasteride decreased prostate cancer risk. Androstenedione is the second most important circulating androgen in men besides testosterone and also a substrate for 5α-reductase enzyme.We observed a 22% increase in androstenedione levels compared with the baseline values in subjects who were treated with finasteride for 3 years. This significant increase did not vary by case-control status. Adjusted odds ratio and 95% confidence interval for the third tertile of absolute change in androstenedione levels compared with the first tertile were 0.42 (95% confidence interval, 0.19-0.94) for low-grade (Gleason score <7) cases. Similar results were observed when analyzed using percent change. There were no significant associations between serum androstenedione levels and the risk of high-grade disease.The results of this nested case-control study confirm that finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT) and of androstenedione to 5α-androstanedione-3,17-dione, which also leads to the reduction of DHT formation. This decrease in DHT may help reduce the risk of low-grade prostate cancer in men. Our data on a differential effect of androstenedione also suggest that some high-grade prostate cancers may not require androgen for progression.

    View details for DOI 10.1016/j.urology.2014.11.024

    View details for Web of Science ID 000351942400034

    View details for PubMedID 25733274

  • Tobacco and Alcohol in Relation to Male Breast Cancer: An Analysis of the Male Breast Cancer Pooling Project Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Cook, M. B., Guenel, P., Gapstur, S. M., van den Brandt, P. A., Michels, K. B., Casagrande, J. T., Cooke, R., Van Den Eeden, S. K., Ewertz, M., Falk, R. T., Gaudet, M. M., Gkiokas, G., Habel, L. A., Hsing, A. W., Johnson, K., Kolonel, L. N., La Vecchia, C., Lynge, E., Lubin, J. H., McCormack, V. A., Negri, E., Olsson, H., Parisi, D., Petridou, E. T., Riboli, E., Sesso, H. D., Swerdlow, A., Thomas, D. B., Willett, W. C., Brinton, L. A. 2015; 24 (3): 520-531
  • Tobacco and alcohol in relation to male breast cancer: an analysis of the male breast cancer pooling project consortium. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Cook, M. B., Guénel, P., Gapstur, S. M., van den Brandt, P. A., Michels, K. B., Casagrande, J. T., Cooke, R., Van Den Eeden, S. K., Ewertz, M., Falk, R. T., Gaudet, M. M., Gkiokas, G., Habel, L. A., Hsing, A. W., Johnson, K., Kolonel, L. N., La Vecchia, C., Lynge, E., Lubin, J. H., McCormack, V. A., Negri, E., Olsson, H., Parisi, D., Petridou, E. T., Riboli, E., Sesso, H. D., Swerdlow, A., Thomas, D. B., Willett, W. C., Brinton, L. A. 2015; 24 (3): 520-531

    Abstract

    The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined.The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis.Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (>60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97-1.71; OR>0-<7 g/day referent = 1.36; 95% CI, 1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index.In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer.Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer.

    View details for DOI 10.1158/1055-9965.EPI-14-1009

    View details for PubMedID 25515550

  • Generalizability of established prostate cancer risk variants in men of African ancestry. International journal of cancer. Journal international du cancer Han, Y., Signorello, L. B., Strom, S. S., Kittles, R. A., Rybicki, B. A., Stanford, J. L., Goodman, P. J., Berndt, S. I., Carpten, J., Casey, G., Chu, L., Conti, D. V., Rand, K. A., Diver, W. R., Hennis, A. J., John, E. M., Kibel, A. S., Klein, E. A., Kolb, S., Le Marchand, L., Leske, M. C., Murphy, A. B., Neslund-Dudas, C., Park, J. Y., Pettaway, C., Rebbeck, T. R., Gapstur, S. M., Zheng, S. L., Wu, S., Witte, J. S., Xu, J., Isaacs, W., Ingles, S. A., Hsing, A., Easton, D. F., Eeles, R. A., Schumacher, F. R., Chanock, S., Nemesure, B., Blot, W. J., Stram, D. O., Henderson, B. E., Haiman, C. A. 2015; 136 (5): 1210-1217

    Abstract

    Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

    View details for DOI 10.1002/ijc.29066

    View details for PubMedID 25044450

  • Relationship Between Male Pattern Baldness and the Risk of Aggressive Prostate Cancer: An Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial JOURNAL OF CLINICAL ONCOLOGY Zhou, C. K., Pfeiffer, R. M., Cleary, S. D., Hoffman, H. J., Levine, P. H., Chu, L. W., Hsing, A. W., Cook, M. B. 2015; 33 (5): 419-U63

    Abstract

    Male pattern baldness and prostate cancer appear to share common pathophysiologic mechanisms. However, results from previous studies that assess their relationship have been inconsistent. Therefore, we investigated the association of male pattern baldness at age 45 years with risks of overall and subtypes of prostate cancer in a large, prospective cohort—the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.We included 39,070 men from the usual care and screening arms of the trial cohort who had no cancer diagnosis (excluding nonmelanoma skin cancer) at the start of follow-up and recalled their hair-loss patterns at age 45 years. Hazard ratios (HRs) and 95% CIs were estimated by using Cox proportional hazards regression models with age as the time metric.During follow-up (median, 2.78 years), 1,138 incident prostate cancer cases were diagnosed, 571 of which were aggressive (biopsy Gleason score ≥ 7, and/or clinical stage III or greater, and/or fatal). Compared with no baldness, frontal plus moderate vertex baldness at age 45 years was not significantly associated with overall (HR, 1.19; 95% CI, 0.98 to 1.45) or nonaggressive (HR, 0.97; 95% CI, 0.72 to 1.30) prostate cancer risk but was significantly associated with increased risk of aggressive prostate cancer (HR, 1.39; 95% CI, 1.07 to 1.80). Adjustment for covariates did not substantially alter these estimates. Other classes of baldness were not significantly associated with overall or subtypes of prostate cancer.Our analysis indicates that frontal plus moderate vertex baldness at age 45 years is associated with an increased risk of aggressive prostate cancer and supports the possibility of common pathophysiologic mechanisms.

    View details for DOI 10.1200/JCO.2014.55.4279

    View details for Web of Science ID 000352458200011

    View details for PubMedID 25225425

  • Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults. PloS one Chen, F., He, J., Zhang, J., Chen, G. K., Thomas, V., Ambrosone, C. B., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Cai, Q., Carpten, J., Casey, G., Chanock, S. J., Cheng, I., Chu, L., Deming, S. L., Driver, W. R., Goodman, P., Hayes, R. B., Hennis, A. J., Hsing, A. W., Hu, J. J., Ingles, S. A., John, E. M., Kittles, R. A., Kolb, S., Leske, M. C., Millikan, R. C., Monroe, K. R., Murphy, A., Nemesure, B., Neslund-Dudas, C., Nyante, S., Ostrander, E. A., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schumacher, F., Stanford, J. L., Signorello, L. B., Strom, S. S., Stevens, V., Van Den Berg, D., Wang, Z., Witte, J. S., Wu, S., Yamamura, Y., Zheng, W., Ziegler, R. G., Stram, A. H., Kolonel, L. N., Le Marchand, L., Henderson, B. E., Haiman, C. A., Stram, D. O. 2015; 10 (6)

    Abstract

    Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

    View details for DOI 10.1371/journal.pone.0131106

    View details for PubMedID 26125186

  • Finasteride concentrations and prostate cancer risk: results from the Prostate Cancer Prevention Trial. PloS one Chau, C. H., Price, D. K., Till, C., Goodman, P. J., Chen, X., Leach, R. J., Johnson-Pais, T. L., Hsing, A. W., Hoque, A., Tangen, C. M., Chu, L., Parnes, H. L., Schenk, J. M., Reichardt, J. K., Thompson, I. M., Figg, W. D. 2015; 10 (5)

    Abstract

    In the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer by 25%, even though high-grade prostate cancer was more common in the finasteride group. However, it remains to be determined whether finasteride concentrations may affect prostate cancer risk. In this study, we examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations.Data for this nested case-control study are from the PCPT. Cases were drawn from men with biopsy-proven prostate cancer and matched controls. Finasteride concentrations were measured using a liquid chromatography-mass spectrometry validated assay. The association of serum finasteride concentrations with prostate cancer risk was determined by logistic regression. We also examine whether polymorphisms in the enzyme target and metabolism genes of finasteride are related to drug concentrations using linear regression.Among men with detectable finasteride concentrations, there was no association between finasteride concentrations and prostate cancer risk, low-grade or high-grade, when finasteride concentration was analyzed as a continuous variable or categorized by cutoff points. Since there was no concentration-dependent effect on prostate cancer, any exposure to finasteride intake may reduce prostate cancer risk. Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway.ClinicalTrials.gov NCT00288106.

    View details for DOI 10.1371/journal.pone.0126672

    View details for PubMedID 25955319

  • Prospective study of human herpesvirus type 8 serostatus and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial CANCER CAUSES & CONTROL Sutcliffe, S., Till, C., Jenkins, F. J., Gaydos, C. A., Goodman, P. J., Hoque, A. M., Hsing, A. W., Thompson, I. M., Nelson, W. G., De Marzo, A. M., Platz, E. A. 2015; 26 (1): 35-44

    Abstract

    Human herpesvirus type 8 (HHV-8), a gamma herpesvirus associated with Kaposi's sarcoma, has been proposed as a candidate risk factor for prostate cancer (PCa) because of its detection in benign and malignant prostate specimens, and its relation with histologic prostatic inflammation. We investigated the possible relation between pre-diagnostic HHV-8 infection and PCa risk in a case-control study sampled from the placebo arm of the Prostate Cancer Prevention Trial.We defined cases as men with a confirmed diagnosis of PCa after visit 2 (n = 315) and controls as men not diagnosed with PCa during the trial who also had a negative end-of-study prostate biopsy (n = 315). We tested sera from visit 2 for IgG antibodies against HHV-8 using a monoclonal antibody-enhanced immunofluorescence assay against multiple lytic HHV-8 antigens.The adjusted seroprevalence of HHV-8 infection was 11.6 % for cases and 11.0 % for controls (p = 0.81). No association was observed between HHV-8 seropositivity and PCa risk (OR 1.06, 95 % CI 0.65-1.76).Our findings of a null association between HHV-8 seropositivity and PCa risk do not support an association between HHV-8 infection and PCa development, consistent with the general tendency of the epidemiologic literature to date.

    View details for DOI 10.1007/s10552-014-0480-5

    View details for Web of Science ID 000347281800004

    View details for PubMedCentralID PMC4282945

  • Non-Steroidal Anti-Inflammatory Drugs Use Is Associated with Reduced Risk of Inflammation-Associated Cancers: NIH-AARP Study PLOS ONE Shebl, F. M., Hsing, A. W., Park, Y., Hollenbeck, A. R., Chu, L. W., Meyer, T. E., Koshiol, J. 2014; 9 (12)

    Abstract

    Chronic inflammation has been linked to cancers, and use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of several cancers. To further refine the magnitude of NSAID-related associations, in particular for cancers related to inflammation, such as alcohol-, infection-, obesity-, and smoking-related cancers, as well as for less common cancers, we evaluated the use of NSAIDs and cancer risk in a very large cohort. We used propensity scores to account for potential selection bias and hypothesized that NSAID use is associated with decreased cancer incidence.We conducted a prospective study among 314,522 participants in the NIH-AARP Diet and Health Study. Individuals who completed the lifestyle questionnaire, which included NSAID use, in 1996-1997 were followed through 2006. Information on cancer incidence was ascertained by linking to cancer registries and vital status databases.During 2,715,994 person-years of follow-up (median 10.1 person-years), there were 51,894 incident cancers. Compared with non-users of NSAIDs, individuals who reported use in the 12 months prior to interview had a significantly lower risk of all inflammation-related cancer, alcohol-related, infection-related, obesity-related, and smoking-related cancers [hazard ratio (HR) (95% CI)) 0.90 (0.87-0.93), 0.80 (0.74-0.85), 0.82 (0.78-0.87), 0.88 (0.84-0.92), and 0.88 (0.85-0.92) respectively)].After accounting for potential selection bias, our data showed an inverse association between NSAID use and alcohol-related, infection-related, obesity-related, and smoking-related cancers and support the hypothesis that inflammation is related to an increased risk of certain cancers.

    View details for DOI 10.1371/journal.pone.0114633

    View details for Web of Science ID 000347119100013

    View details for PubMedCentralID PMC4281259

  • Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33. Human molecular genetics Wang, Z., Zhu, B., Zhang, M., Parikh, H., Jia, J., Chung, C. C., Sampson, J. N., Hoskins, J. W., Hutchinson, A., Burdette, L., Ibrahim, A., Hautman, C., Raj, P. S., Abnet, C. C., Adjei, A. A., Ahlbom, A., Albanes, D., Allen, N. E., Ambrosone, C. B., Aldrich, M., Amiano, P., Amos, C., Andersson, U., Andriole, G., Andrulis, I. L., Arici, C., Arslan, A. A., Austin, M. A., Baris, D., Barkauskas, D. A., Bassig, B. A., Beane Freeman, L. E., Berg, C. D., Berndt, S. I., Bertazzi, P. A., Biritwum, R. B., Black, A., Blot, W., Boeing, H., Boffetta, P., Bolton, K., Boutron-Ruault, M., Bracci, P. M., Brennan, P., Brinton, L. A., Brotzman, M., Bueno-de-Mesquita, H. B., Buring, J. E., Butler, M. A., Cai, Q., Cancel-Tassin, G., Canzian, F., Cao, G., Caporaso, N. E., Carrato, A., Carreon, T., Carta, A., Chang, G., Chang, I., Chang-Claude, J., Che, X., Chen, C., Chen, C., Chen, C., Chen, C., Chen, K., Chen, Y., Chokkalingam, A. P., Chu, L. W., Clavel-Chapelon, F., Colditz, G. A., Colt, J. S., Conti, D., Cook, M. B., Cortessis, V. K., Crawford, E. D., Cussenot, O., Davis, F. G., De Vivo, I., Deng, X., Ding, T., Dinney, C. P., Di Stefano, A. L., Diver, W. R., Duell, E. J., Elena, J. W., Fan, J., Feigelson, H. S., Feychting, M., Figueroa, J. D., Flanagan, A. M., Fraumeni, J. F., Freedman, N. D., Fridley, B. L., Fuchs, C. S., Gago-Dominguez, M., Gallinger, S., Gao, Y., Gapstur, S. M., Garcia-Closas, M., Garcia-Closas, R., Gastier-Foster, J. M., Gaziano, J. M., Gerhard, D. S., Giffen, C. A., Giles, G. G., Gillanders, E. M., Giovannucci, E. L., Goggins, M., Gokgoz, N., Goldstein, A. M., Gonzalez, C., Gorlick, R., Greene, M. H., Gross, M., Grossman, H. B., Grubb, R., Gu, J., Guan, P., Haiman, C. A., Hallmans, G., Hankinson, S. E., Harris, C. C., Hartge, P., Hattinger, C., Hayes, R. B., He, Q., Helman, L., Henderson, B. E., Henriksson, R., Hoffman-Bolton, J., Hohensee, C., Holly, E. A., Hong, Y., Hoover, R. N., Hosgood, H. D., Hsiao, C., Hsing, A. W., Hsiung, C. A., Hu, N., Hu, W., Hu, Z., Huang, M., Hunter, D. J., Inskip, P. D., Ito, H., Jacobs, E. J., Jacobs, K. B., Jenab, M., Ji, B., Johansen, C., Johansson, M., Johnson, A., Kaaks, R., Kamat, A. M., Kamineni, A., Karagas, M., Khanna, C., Khaw, K., Kim, C., Kim, I., Kim, J. H., Kim, Y. H., Kim, Y., Kim, Y. T., Kang, C. H., Jung, Y. J., Kitahara, C. M., Klein, A. P., Klein, R., Kogevinas, M., Koh, W., Kohno, T., Kolonel, L. N., Kooperberg, C., Kratz, C. P., Krogh, V., Kunitoh, H., Kurtz, R. C., Kurucu, N., Lan, Q., Lathrop, M., Lau, C. C., Lecanda, F., Lee, K., Lee, M. P., Le Marchand, L., Lerner, S. P., Li, D., Liao, L. M., Lim, W., Lin, D., Lin, J., Lindstrom, S., Linet, M. S., Lissowska, J., Liu, J., Ljungberg, B., Lloreta, J., Lu, D., Ma, J., Malats, N., Mannisto, S., Marina, N., Mastrangelo, G., Matsuo, K., McGlynn, K. A., McKean-Cowdin, R., McNeill, L. H., Mcwilliams, R. R., Melin, B. S., Meltzer, P. S., Mensah, J. E., Miao, X., Michaud, D. S., Mondul, A. M., Moore, L. E., Muir, K., Niwa, S., Olson, S. H., Orr, N., Panico, S., Park, J. Y., Patel, A. V., Patino-Garcia, A., Pavanello, S., Peeters, P. H., Peplonska, B., Peters, U., Petersen, G. M., Picci, P., Pike, M. C., Porru, S., Prescott, J., Pu, X., Purdue, M. P., Qiao, Y., Rajaraman, P., Riboli, E., Risch, H. A., Rodabough, R. J., Rothman, N., Ruder, A. M., Ryu, J., Sanson, M., Schned, A., Schumacher, F. R., Schwartz, A. G., Schwartz, K. L., Schwenn, M., Scotlandi, K., Seow, A., Serra, C., Serra, M., Sesso, H. D., Severi, G., Shen, H., Shen, M., Shete, S., Shiraishi, K., Shu, X., Siddiq, A., Sierrasesumaga, L., Sierri, S., Loon Sihoe, A. D., Silverman, D. T., Simon, M., Southey, M. C., Spector, L., Spitz, M., Stampfer, M., Stattin, P., Stern, M. C., Stevens, V. L., Stolzenberg-Solomon, R. Z., Stram, D. O., Strom, S. S., Su, W., Sund, M., Sung, S. W., Swerdlow, A., Tan, W., Tanaka, H., Tang, W., Tang, Z., Tardon, A., Tay, E., Taylor, P. R., Tettey, Y., Thomas, D. M., Tirabosco, R., Tjonneland, A., Tobias, G. S., Toro, J. R., Travis, R. C., Trichopoulos, D., Troisi, R., Truelove, A., Tsai, Y., Tucker, M. A., Tumino, R., Van Den Berg, D., Van Den Eeden, S. K., Vermeulen, R., Vineis, P., Visvanathan, K., Vogel, U., Wang, C., Wang, C., Wang, J., Wang, S. S., Weiderpass, E., Weinstein, S. J., Wentzensen, N., Wheeler, W., White, E., Wiencke, J. K., Wolk, A., Wolpin, B. M., Wong, M. P., Wrensch, M., Wu, C., Wu, T., Wu, X., Wu, Y., Wunder, J. S., Xiang, Y., Xu, J., Yang, H. P., Yang, P., Yatabe, Y., Ye, Y., Yeboah, E. D., Yin, Z., Ying, C., Yu, C., Yu, K., Yuan, J., Zanetti, K. A., Zeleniuch-Jacquotte, A., Zheng, W., Zhou, B., Mirabello, L., Savage, S. A., Kraft, P., Chanock, S. J., Yeager, M., Landi, M. T., Shi, J., Chatterjee, N., Amundadottir, L. T. 2014; 23 (24): 6616-6633

    Abstract

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

    View details for DOI 10.1093/hmg/ddu363

    View details for PubMedID 25027329

  • Variants in motilin, somatostatin and their receptor genes and risk of biliary tract cancers and stones in Shanghai, China. Meta gene Xu, H., Hsing, A. W., Koshiol, J., Chu, L. W., Cheng, J., Gao, J., Tan, Y., Wang, B., Shen, M., Gao, Y. 2014; 2: 418-426

    Abstract

    Altered motility of the gallbladder can result in gallstone and cholecystitis, which are important risk factor for biliary tract cancer. Motilin (MLN) and somatostatin (SST) are known important modulators of gallbladder motility. To determine whether genetic variants in motilin, somatostatin, and their receptor genes are associated with the risk of biliary tract cancers and stones, nine tag-SNPs were determined in 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct and 53 ampulla of Vater cancer cases), 429 biliary stone cases, and 447 population controls in a population-based case-control study in Shanghai, China. We found that subjects with the MLNR rs9568169 AA genotype and SSTR5 rs169068 CC genotype were significantly associated with risk of extrahepatic bile duct cancer (OR =0.49, 95% CI: 0.27-0.89; OR =2.40, 95% CI: 1.13-5.13) compared to the major genotypes. MLN rs2281820 CT and rs3793079 AT genotypes had significantly increased risks of gallstones (OR =1.52, 95% CI: 1.06-2.18; OR =1.64, 95% CI: 1.20-2.25) compared to TT genotypes. Besides, Haplotype analysis showed that MLN T-T-T haplotype (rs2281820-rs3793079-rs2281819) had a non-significantly elevated risk of gallstone (OR =1.30, 95% CI: 0.91-1.86) compared with C-A-A haplotype. To the best of our knowledge, this is the first study to report an association between genetic polymorphisms in MLN, MLNR and their receptor genes and risk of biliary tract cancers and stones.

    View details for PubMedID 24999450

    View details for PubMedCentralID PMC4080205

  • Leveraging population admixture to characterize the heritability of complex traits NATURE GENETICS Zaitlen, N., Pasaniuc, B., Sankararaman, S., Bhatia, G., Zhang, J., Gusev, A., Young, T., Tandon, A., Pollack, S., Vilhjalmsson, B. J., Assimes, T. L., Berndt, S. I., Blot, W. J., Chanock, S., Franceschini, N., Goodman, P. G., He, J., Hennis, A. J., Hsing, A., Ingles, S. A., Isaacs, W., Kittles, R. A., Klein, E. A., Lange, L. A., Nemesure, B., Patterson, N., Reich, D., Rybicki, B. A., Stanford, J. L., Stevens, V. L., Strom, S. S., Whitse, E. A., Witte, J. S., Xu, J., Haiman, C., Wilson, J. G., Kooperberg, C., Stram, D., Reiner, A. P., Tang, H., Price, A. L. 2014; 46 (12): 1356-1362

    Abstract

    Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2).

    View details for DOI 10.1038/ng.3139

    View details for Web of Science ID 000345547300019

    View details for PubMedCentralID PMC4244251

  • Leveraging population admixture to characterize the heritability of complex traits. Nature genetics Zaitlen, N., Pasaniuc, B., Sankararaman, S., Bhatia, G., Zhang, J., Gusev, A., Young, T., Tandon, A., Pollack, S., Vilhjálmsson, B. J., Assimes, T. L., Berndt, S. I., Blot, W. J., Chanock, S., Franceschini, N., Goodman, P. G., He, J., Hennis, A. J., Hsing, A., Ingles, S. A., Isaacs, W., Kittles, R. A., Klein, E. A., Lange, L. A., Nemesure, B., Patterson, N., Reich, D., Rybicki, B. A., Stanford, J. L., Stevens, V. L., Strom, S. S., Whitsel, E. A., Witte, J. S., Xu, J., Haiman, C., Wilson, J. G., Kooperberg, C., Stram, D., Reiner, A. P., Tang, H., Price, A. L. 2014; 46 (12): 1356-1362

    Abstract

    Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2).

    View details for DOI 10.1038/ng.3139

    View details for PubMedID 25383972

    View details for PubMedCentralID PMC4244251

  • Sex Steroid Hormone Metabolism in Relation to Risk of Aggressive Prostate Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Black, A., Pinsky, P. F., Grubb, R. L., Falk, R. T., Hsing, A. W., Chu, L., Meyer, T., Veenstra, T. D., Xu, X., Yu, K., Ziegler, R. G., Brinton, L. A., Hoover, R. N., Cook, M. B. 2014; 23 (11): 2374-2382

    Abstract

    The combined action of androgens and estrogens-specifically their balance-may play a role in prostate carcinogenesis, but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer.In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort, we measured serum estrone, estradiol, and 13 estrogen metabolites, in the 2-, 4-, or 16-hydroxylation pathways, using an LC/MS-MS assay. Cases (n = 195) were non-Hispanic white men ages 55 to 70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7). Controls (n = 195) were non-Hispanic white men without prostate cancer who were frequency matched to cases by age and year at blood draw, and time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate ORs and 95% confidence intervals (95% CI).Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone ratio (OR4th quartile vs. 1st = 0.27; 95% CI, 0.12-0.59, Ptrend = 0.003) and positively associated with 2:16α-hydroxyestrone ratio (OR4th quartile vs. 1st = 2.44; 95% CI, 1.34-4.45, Ptrend = 0.001). Individual estrogen metabolites were unrelated to risk.Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer.Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions.

    View details for DOI 10.1158/1055-9965.EPI-14-0700

    View details for Web of Science ID 000345279600020

    View details for PubMedCentralID PMC4221438

  • Cancer Research in Asian American, Native Hawaiian, and Pacific Islander Populations: Accelerating Cancer Knowledge by Acknowledging and Leveraging Heterogeneity CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gomez, S. L., Glaser, S. L., Horn-Ross, P. L., Cheng, I., Quach, T., Clarke, C. A., Reynolds, P., Shariff-Marco, S., Yang, J., Lee, M. M., Satariano, W. A., Hsing, A. W. 2014; 23 (11): 2202-2205

    Abstract

    The Asian American, Native Hawaiian, and Pacific Islander population is large, growing, and extremely heterogeneous. Not only do they bear unique burdens of incidence and outcomes for certain cancer types, they exhibit substantial variability in cancer incidence and survival patterns across the ethnic groups. By acknowledging and leveraging this heterogeneity through investing in cancer research within these populations, we have a unique opportunity to accelerate the availability of useful and impactful cancer knowledge. See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations." Cancer Epidemiol Biomarkers Prev; 23(11); 2202-5. ©2014 AACR.

    View details for DOI 10.1158/1055-9965.EPI-14-0624

    View details for Web of Science ID 000345279600001

  • Cancer research in Asian American, Native Hawaiian, and Pacific Islander populations: accelerating cancer knowledge by acknowledging and leveraging heterogeneity. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Gomez, S. L., Glaser, S. L., Horn-Ross, P. L., Cheng, I., Quach, T., Clarke, C. A., Reynolds, P., Shariff-Marco, S., Yang, J., Lee, M. M., Satariano, W. A., Hsing, A. W. 2014; 23 (11): 2202-2205

    Abstract

    The Asian American, Native Hawaiian, and Pacific Islander population is large, growing, and extremely heterogeneous. Not only do they bear unique burdens of incidence and outcomes for certain cancer types, they exhibit substantial variability in cancer incidence and survival patterns across the ethnic groups. By acknowledging and leveraging this heterogeneity through investing in cancer research within these populations, we have a unique opportunity to accelerate the availability of useful and impactful cancer knowledge. See all the articles in this CEBP Focus section, "Cancer in Asian and Pacific Islander Populations." Cancer Epidemiol Biomarkers Prev; 23(11); 2202-5. ©2014 AACR.

    View details for DOI 10.1158/1055-9965.EPI-14-0624

    View details for PubMedID 25368394

  • Sex steroid hormone metabolism in relation to risk of aggressive prostate cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Black, A., Pinsky, P. F., Grubb, R. L., Falk, R. T., Hsing, A. W., Chu, L., Meyer, T., Veenstra, T. D., Xu, X., Yu, K., Ziegler, R. G., Brinton, L. A., Hoover, R. N., Cook, M. B. 2014; 23 (11): 2374-2382

    Abstract

    The combined action of androgens and estrogens-specifically their balance-may play a role in prostate carcinogenesis, but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer.In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort, we measured serum estrone, estradiol, and 13 estrogen metabolites, in the 2-, 4-, or 16-hydroxylation pathways, using an LC/MS-MS assay. Cases (n = 195) were non-Hispanic white men ages 55 to 70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7). Controls (n = 195) were non-Hispanic white men without prostate cancer who were frequency matched to cases by age and year at blood draw, and time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate ORs and 95% confidence intervals (95% CI).Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone ratio (OR4th quartile vs. 1st = 0.27; 95% CI, 0.12-0.59, Ptrend = 0.003) and positively associated with 2:16α-hydroxyestrone ratio (OR4th quartile vs. 1st = 2.44; 95% CI, 1.34-4.45, Ptrend = 0.001). Individual estrogen metabolites were unrelated to risk.Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer.Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions.

    View details for DOI 10.1158/1055-9965.EPI-14-0700

    View details for PubMedID 25178985

  • A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer NATURE GENETICS Al Olama, A. A., Kote-Jarai, Z., Berndt, S. I., Conti, D. V., Schumacher, F., Han, Y., Benlloch, S., Hazelett, D. J., Wang, Z., Saunders, E., Leongamornlert, D., Lindstrom, S., Jugurnauth-Little, S., Dadaev, T., Tymrakiewicz, M., Stram, D. O., Rand, K., Wan, P., Stram, A., Sheng, X., Pooler, L. C., Park, K., Xia, L., Tyrer, J., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Goh, C., Ahmed, M., Govindasami, K., Guy, M., Tammela, T. L., Auvinen, A., Wahlfors, T., Schleutker, J., Visakorpi, T., Leinonen, K. A., Xu, J., Aly, M., Donovan, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Khaw, K., Takahashi, A., Kubo, M., Pharoah, P., Pashayan, N., Weischer, M., Nordestgaard, B. G., Nielsen, S. F., Klarskov, P., Roder, M. A., Iversen, P., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Stanford, J. L., Kolb, S., Holt, S., Knudsen, B., Coll, A. H., Gapstur, S. M., Diver, W. R., Stevens, V. L., Maier, C., Luedeke, M., Herkommer, K., Rinckleb, A. E., Strom, S. S., Pettaway, C., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Choklcalingam, A. P., Cannon-Albright, L., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Park, J., Sellers, T., Lin, H., Isaacs, W. B., Partin, A. W., Brenner, H., Dieffenbach, A. K., Stegmaier, C., Chen, C., Giovannucci, E. L., Ma, J., Stampfer, M., Penney, K. L., Mucci, L., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Pandha, H., Michael, A., Kierzek, A. M., Blot, W., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, C., Wu, S., Hennis, A., Kibel, A. S., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Batra, J., Clements, J., Spurdle, A., Teixeira, M. R., Paulo, P., Maia, S., Slavov, C., Kaneva, R., Mitev, V., Witte, J. S., Casey, G., Gillanders, E. M., Seminara, D., Riboli, E., Hamdy, F. C., Coetzee, G. A., Li, Q., Freedman, M. L., Hunter, D. J., Muir, K., Gronberg, H., Nea, D. E., Southey, M., Giles, G. G., Severi, G., Cook, M. B., Nakagawa, H., Wiklund, F., Kraft, P., Chanock, S. J., Henderson, B. E., Easton, D. F., Eeles, R. A., Haiman, C. A. 2014; 46 (10): 1103-1109

    Abstract

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

    View details for DOI 10.1038/ng.3094

    View details for Web of Science ID 000342554100013

  • A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nature genetics Al Olama, A. A., Kote-Jarai, Z., Berndt, S. I., Conti, D. V., Schumacher, F., Han, Y., Benlloch, S., Hazelett, D. J., Wang, Z., Saunders, E., Leongamornlert, D., Lindstrom, S., Jugurnauth-Little, S., Dadaev, T., Tymrakiewicz, M., Stram, D. O., Rand, K., Wan, P., Stram, A., Sheng, X., Pooler, L. C., Park, K., Xia, L., Tyrer, J., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Goh, C., Ahmed, M., Govindasami, K., Guy, M., Tammela, T. L., Auvinen, A., Wahlfors, T., Schleutker, J., Visakorpi, T., Leinonen, K. A., Xu, J., Aly, M., Donovan, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Khaw, K., Takahashi, A., Kubo, M., Pharoah, P., Pashayan, N., Weischer, M., Nordestgaard, B. G., Nielsen, S. F., Klarskov, P., Røder, M. A., Iversen, P., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Stanford, J. L., Kolb, S., Holt, S., Knudsen, B., Coll, A. H., Gapstur, S. M., Diver, W. R., Stevens, V. L., Maier, C., Luedeke, M., Herkommer, K., Rinckleb, A. E., Strom, S. S., Pettaway, C., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., Cannon-Albright, L., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Park, J., Sellers, T., Lin, H., Isaacs, W. B., Partin, A. W., Brenner, H., Dieffenbach, A. K., Stegmaier, C., Chen, C., Giovannucci, E. L., Ma, J., Stampfer, M., Penney, K. L., Mucci, L., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Pandha, H., Michael, A., Kierzek, A. M., Blot, W., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, C., Wu, S., Hennis, A., Kibel, A. S., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Batra, J., Clements, J., Spurdle, A., Teixeira, M. R., Paulo, P., Maia, S., Slavov, C., Kaneva, R., Mitev, V., Witte, J. S., Casey, G., Gillanders, E. M., Seminara, D., Riboli, E., Hamdy, F. C., Coetzee, G. A., Li, Q., Freedman, M. L., Hunter, D. J., Muir, K., Gronberg, H., Neal, D. E., Southey, M., Giles, G. G., Severi, G., Cook, M. B., Nakagawa, H., Wiklund, F., Kraft, P., Chanock, S. J., Henderson, B. E., Easton, D. F., Eeles, R. A., Haiman, C. A. 2014; 46 (10): 1103-1109

    Abstract

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

    View details for DOI 10.1038/ng.3094

    View details for PubMedID 25217961

  • High Prevalence of Screen Detected Prostate Cancer in West Africans: Implications for Racial Disparity of Prostate Cancer JOURNAL OF UROLOGY Hsing, A. W., Yeboah, E., Biritwum, R., Tettey, Y., De Marzo, A. M., Adjei, A., Netto, G. J., Yu, K., Li, Y., Chokkalingam, A. P., Chu, L. W., Chia, D., Partin, A., Thompson, I. M., Quraishi, S. M., Niwa, S., Tarone, R., Hoover, R. N. 2014; 192 (3): 730-735

    Abstract

    To our knowledge the reasons for the high rates of prostate cancer in black American men are unknown. Genetic and lifestyle factors have been implicated. Better understanding of prostate cancer rates in West African men would help clarify why black American men have such high rates since the groups share genetic ancestry and yet have different lifestyles and screening practices. To estimate the prostate cancer burden in West African men we performed a population based screening study with biopsy confirmation in Ghana.We randomly selected 1,037 healthy men 50 to 74 years old from Accra, Ghana for prostate cancer screening with prostate specific antigen testing and digital rectal examination. Men with a positive screen result (positive digital rectal examination or prostate specific antigen greater than 2.5 ng/ml) underwent transrectal ultrasound guided biopsies.Of the 1,037 men 154 (14.9%) had a positive digital rectal examination and 272 (26.2%) had prostate specific antigen greater than 2.5 ng/ml, including 166 with prostate specific antigen greater than 4.0 ng/ml. A total of 352 men (33.9%) had a positive screen by prostate specific antigen or digital rectal examination and 307 (87%) underwent biopsy. Of these men 73 were confirmed to have prostate cancer, yielding a 7.0% screen detected prostate cancer prevalence (65 patients), including 5.8% with prostate specific antigen greater than 4.0 ng/ml.In this relatively unscreened population in Africa the screen detected prostate cancer prevalence is high, suggesting a possible role of genetics in prostate cancer etiology and the disparity in prostate cancer risk between black and white American men. Further studies are needed to confirm the high prostate cancer burden in African men and the role of genetics in prostate cancer etiology.

    View details for DOI 10.1016/j.juro.2014.04.017

    View details for Web of Science ID 000342105600028

    View details for PubMedCentralID PMC4332806

  • High prevalence of screen detected prostate cancer in West Africans: implications for racial disparity of prostate cancer. journal of urology Hsing, A. W., Yeboah, E., Biritwum, R., Tettey, Y., De Marzo, A. M., Adjei, A., Netto, G. J., Yu, K., Li, Y., Chokkalingam, A. P., Chu, L. W., Chia, D., Partin, A., Thompson, I. M., Quraishi, S. M., Niwa, S., Tarone, R., Hoover, R. N. 2014; 192 (3): 730-735

    Abstract

    To our knowledge the reasons for the high rates of prostate cancer in black American men are unknown. Genetic and lifestyle factors have been implicated. Better understanding of prostate cancer rates in West African men would help clarify why black American men have such high rates since the groups share genetic ancestry and yet have different lifestyles and screening practices. To estimate the prostate cancer burden in West African men we performed a population based screening study with biopsy confirmation in Ghana.We randomly selected 1,037 healthy men 50 to 74 years old from Accra, Ghana for prostate cancer screening with prostate specific antigen testing and digital rectal examination. Men with a positive screen result (positive digital rectal examination or prostate specific antigen greater than 2.5 ng/ml) underwent transrectal ultrasound guided biopsies.Of the 1,037 men 154 (14.9%) had a positive digital rectal examination and 272 (26.2%) had prostate specific antigen greater than 2.5 ng/ml, including 166 with prostate specific antigen greater than 4.0 ng/ml. A total of 352 men (33.9%) had a positive screen by prostate specific antigen or digital rectal examination and 307 (87%) underwent biopsy. Of these men 73 were confirmed to have prostate cancer, yielding a 7.0% screen detected prostate cancer prevalence (65 patients), including 5.8% with prostate specific antigen greater than 4.0 ng/ml.In this relatively unscreened population in Africa the screen detected prostate cancer prevalence is high, suggesting a possible role of genetics in prostate cancer etiology and the disparity in prostate cancer risk between black and white American men. Further studies are needed to confirm the high prostate cancer burden in African men and the role of genetics in prostate cancer etiology.

    View details for DOI 10.1016/j.juro.2014.04.017

    View details for PubMedID 24747091

  • Diabetes Mellitus and Risk of Thyroid Cancer: A Meta-Analysis PLOS ONE Yeo, Y., Ma, S., Hwang, Y., Horn-Ross, P. L., Hsing, A., Lee, K., Park, Y. J., Park, D., Yoo, K., Park, S. K. 2014; 9 (6)

    Abstract

    Diabetes mellitus (DM) is an important risk factor for endocrine cancers; however, the association with thyroid cancer is not clear. We performed a systematic review and meta-analysis to clarify the association between thyroid cancer and DM.We searched MEDLINE, PUBMED and EMBASE databases through July 2012, using search terms related to diabetes mellitus, cancer, and thyroid cancer. We conducted a meta-analysis of the risk of incidence of thyroid cancer from pre-existing diabetes. Of 2,123 titles initially identified, sixteen articles met our inclusion criteria. An additional article was identified from a bibliography. Totally, 14 cohort and 3 case-control studies were selected for the meta-analysis. The risks were estimated using random-effects model and sensitivity test for the studies which reported risk estimates and used different definition of DM.Compared with individuals without DM, the patients with DM were at 1.34-fold higher risk for thyroid cancer (95% CI 1.11-1.63). However, there was heterogeneity in the results (p<0.0001). Sensitivity tests and studies judged to be high quality did not show heterogeneity and DM was associated with higher risk for thyroid cancer in these sub-analyses (both of RRs = 1.18, 95% CIs 1.08-1.28). DM was associated with a 1.38-fold increased risk of thyroid cancer in women (95% CI 1.13-1.67) after sensitivity test. Risk of thyroid cancer in men did not remain significant (RR 1.11, 95% CI 0.80-1.53).Compared with their non-diabetic counterparts, women with pre-existing DM have an increased risk of thyroid cancer.

    View details for DOI 10.1371/journal.pone.0098135

    View details for Web of Science ID 000338278100012

    View details for PubMedID 24927125

  • Insulin-like Growth Factor Pathway Genetic Polymorphisms, Circulating IGF1 and IGFBP3, and Prostate Cancer Survival JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Cao, Y., Lindstroem, S., Schumacher, F., Stevens, V. L., Albanes, D., Berndt, S. I., Boeing, H., Bueno-de-Mesquita, H. B., Canzian, F., Chamosa, S., Chanock, S. J., Diver, W. R., Gapstur, S. M., Gaziano, J. M., Giovannucci, E. L., Haiman, C. A., Henderson, B., Johansson, M., Le Marchand, L., Palli, D., Rosner, B., Siddiq, A., Stampfer, M., Stram, D. O., Tamimi, R., Travis, R. C., Trichopoulos, D., Willett, W. C., Yeager, M., Kraft, P., Hsing, A. W., Pollak, M., Lin, X., Ma, J. 2014; 106 (6)

    Abstract

    The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

    View details for DOI 10.1093/jnci/dju085

    View details for Web of Science ID 000341636800003

    View details for PubMedCentralID PMC4081624

  • Insulin-like Growth Factor Pathway Genetic Polymorphisms, Circulating IGF1 and IGFBP3, and Prostate Cancer Survival JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Cao, Y., Lindstroem, S., Schumacher, F., Stevens, V. L., Albanes, D., Berndt, S. I., Boeing, H., Bueno-de-Mesquita, H. B., Canzian, F., Chamosa, S., Chanock, S. J., Diver, W. R., Gapstur, S. M., Gaziano, J. M., Giovannucci, E. L., Haiman, C. A., Henderson, B., Johansson, M., Le Marchand, L., Palli, D., Rosner, B., Siddiq, A., Stampfer, M., Stram, D. O., Tamimi, R., Travis, R. C., Trichopoulos, D., Willett, W. C., Yeager, M., Kraft, P., Hsing, A. W., Pollak, M., Lin, X., Ma, J. 2014; 106 (5)
  • A comprehensive resequence-analysis of 250 kb region of 8q24.21 in men of African ancestry PROSTATE Chung, C. C., Hsing, A. W., Yeboah, E., Biritwum, R., Tettey, Y., Adjei, A., Cook, M. B., De Marzo, A., Netto, G., Tay, E., Boland, J. F., Yeager, M., Chanock, S. J. 2014; 74 (6): 579-589

    Abstract

    Genome-wide association studies (GWAS) have identified that a ∼1 M region centromeric to the MYC oncogene on chromosome 8q24.21 harbors at least five independent loci associated with prostate cancer risk and additional loci associated with cancers of breast, colon, bladder, and chronic lymphocytic leukemia (CLL). Because GWAS identify genetic markers that may be indirectly associated with disease, fine-mapping based on sequence analysis provides important insights into patterns of linkage disequilibrium (LD) and is critical in defining the optimal variants to nominate for biological follow-up.To catalog variation in individuals of African ancestry, we resequenced a region (250 kb; chr8:128,050, 768–128, 300,801, hg19) containing several prostate cancer susceptibility loci as well as a locus associated with CLL. Our samples included 78 individuals from Ghana and 47 of African-Americans from Johns Hopkins University.After quality control metrics were applied to next-generation sequence data, 1,838 SNPs were identified. Of these, 285 were novel and not yet reported in any public database. Using genotypes derived from sequencing, we refined the LD and recombination hotspots within the region and determined a set of tag SNPs to be used in future fine-mapping studies. Based on LD, we annotated putative risk loci and their surrogates using ENCODE data, which should help guide laboratory studies.In comparison to the 1000 Genome Project data, we have identified additional variants that could be important in establishing priorities for future functional work designed to explain the biological basis of associations between SNPs and both prostate cancer and CLL.

    View details for DOI 10.1002/pros.22726

    View details for Web of Science ID 000333445500002

    View details for PubMedID 24783269

  • A genome-wide association study of prostate cancer in West African men HUMAN GENETICS Cook, M. B., Wang, Z., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chung, C. C., Chokkalingam, A. P., Chu, L. W., Yeager, M., Hutchinson, A., Yu, K., Rand, K. A., Haiman, C. A., Hoover, R. N., Hsing, A. W., Chanock, S. J. 2014; 133 (5): 509-521

    Abstract

    Age-adjusted mortality rates for prostate cancer are higher for African-American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference. We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip. The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29E-7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p = 3.66E-8), and SNPs at Xq28 (rs985081, p = 8.66E-9) and 6q21 (rs2185710, p = 5.95E-8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p < 0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African-American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p < 0.05. Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.

    View details for DOI 10.1007/s00439-013-1387-z

    View details for Web of Science ID 000334519900004

    View details for PubMedCentralID PMC3988225

  • Anthropometric and hormonal risk factors for male breast cancer: male breast cancer pooling project results. Journal of the National Cancer Institute Brinton, L. A., Cook, M. B., McCormack, V., Johnson, K. C., Olsson, H., Casagrande, J. T., Cooke, R., Falk, R. T., Gapstur, S. M., Gaudet, M. M., Gaziano, J. M., Gkiokas, G., Guénel, P., Henderson, B. E., Hollenbeck, A., Hsing, A. W., Kolonel, L. N., Isaacs, C., Lubin, J. H., Michels, K. B., Negri, E., Parisi, D., Petridou, E. T., Pike, M. C., Riboli, E., Sesso, H. D., Snyder, K., Swerdlow, A. J., Trichopoulos, D., Ursin, G., van den Brandt, P. A., Van Den Eeden, S. K., Weiderpass, E., Willett, W. C., Ewertz, M., Thomas, D. B. 2014; 106 (3): djt465-?

    Abstract

    The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors.In the Male Breast Cancer Pooling Project, a consortium of 11 case-control and 10 cohort investigations involving 2405 case patients (n = 1190 from case-control and n = 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study design-specific (case-control/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided.Risk was statistically significantly associated with weight (highest/lowest tertile: OR = 1.36; 95% CI = 1.18 to 1.57), height (OR = 1.18; 95% CI = 1.01 to 1.38), and body mass index (BMI; OR = 1.30; 95% CI = 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR = 24.7; 95% CI = 8.94 to 68.4) and gynecomastia (OR = 9.78; 95% CI = 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR = 1.29; 95% CI = 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR = 1.41; 95% CI = 1.07 to 1.86).Consistent findings across case-control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones.

    View details for DOI 10.1093/jnci/djt465

    View details for PubMedID 24552677

    View details for PubMedCentralID PMC3975166

  • Anthropometric and Hormonal Risk Factors for Male Breast Cancer: Male Breast Cancer Pooling Project Results JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Brinton, L. A., Cook, M. B., McCormack, V., Johnson, K. C., Olsson, H., Casagrande, J. T., Cooke, R., Falk, R. T., Gapstur, S. M., Gaudet, M. M., Gaziano, J. M., Gkiokas, G., Guenel, P., Henderson, B. E., Hollenbeck, A., Hsing, A. W., Kolonel, L. N., Isaacs, C., Lubin, J. H., Michels, K. B., Negri, E., Parisi, D., Petridou, E. T., Pike, M. C., Riboli, E., Sesso, H. D., Snyder, K., Swerdlow, A. J., Trichopoulos, D., Ursin, G., van den Brandt, P. A., Van Den Eeden, S. K., Weiderpass, E., Willett, W. C., Ewertz, M., Thomas, D. B. 2014; 106 (3)
  • Body mass index and mortality among blacks and whites adults in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial OBESITY Xiao, Q., Hsing, A. W., Park, Y., Moore, S. C., Matthews, C. E., de Gonzalez, A. B., Kitahara, C. M. 2014; 22 (1): 260-268

    Abstract

    In a large prospective cohort, we examined the relationship of body mass index (BMI) with mortality among blacks and compared the results to those among whites in this population.The study population consisted of 7,446 non-Hispanic black and 130,598 white participants, ages 49-78 at enrollment, in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. BMI at baseline, BMI at age 20, and BMI change were calculated using self-reported and recalled height and weight. Relative risks were stratified by race and sex and adjusted for age, education, marital status, and smoking.During follow-up, 1,495 black and 18,236 white participants died (mean = 13 years). Clear J-shaped associations between BMI and mortality were observed among white men and women. Among black men and women, the bottoms of these curves were flatter, and increasing risks of death with greater BMI were observed only at higher BMI levels (≥35.0). Associations for BMI at age 20 and BMI change also appeared to be stronger in magnitude in whites versus blacks, and these racial differences appeared to be more pronounced among women.Our results suggest that BMI may be more weakly associated with mortality in blacks, particularly black women, than in whites.

    View details for DOI 10.1002/oby.20412

    View details for Web of Science ID 000329613600038

    View details for PubMedID 23512729

  • Non-steroidal anti-inflammatory drugs use is associated with reduced risk of inflammation-associated cancers: NIH-AARP study. PloS one Shebl, F. M., Hsing, A. W., Park, Y., Hollenbeck, A. R., Chu, L. W., Meyer, T. E., Koshiol, J. 2014; 9 (12)

    Abstract

    Chronic inflammation has been linked to cancers, and use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of several cancers. To further refine the magnitude of NSAID-related associations, in particular for cancers related to inflammation, such as alcohol-, infection-, obesity-, and smoking-related cancers, as well as for less common cancers, we evaluated the use of NSAIDs and cancer risk in a very large cohort. We used propensity scores to account for potential selection bias and hypothesized that NSAID use is associated with decreased cancer incidence.We conducted a prospective study among 314,522 participants in the NIH-AARP Diet and Health Study. Individuals who completed the lifestyle questionnaire, which included NSAID use, in 1996-1997 were followed through 2006. Information on cancer incidence was ascertained by linking to cancer registries and vital status databases.During 2,715,994 person-years of follow-up (median 10.1 person-years), there were 51,894 incident cancers. Compared with non-users of NSAIDs, individuals who reported use in the 12 months prior to interview had a significantly lower risk of all inflammation-related cancer, alcohol-related, infection-related, obesity-related, and smoking-related cancers [hazard ratio (HR) (95% CI)) 0.90 (0.87-0.93), 0.80 (0.74-0.85), 0.82 (0.78-0.87), 0.88 (0.84-0.92), and 0.88 (0.85-0.92) respectively)].After accounting for potential selection bias, our data showed an inverse association between NSAID use and alcohol-related, infection-related, obesity-related, and smoking-related cancers and support the hypothesis that inflammation is related to an increased risk of certain cancers.

    View details for DOI 10.1371/journal.pone.0114633

    View details for PubMedID 25551641

  • Individual Variations in Serum Melatonin Levels through Time: Implications for Epidemiologic Studies PLOS ONE Nogueira, L. M., Sampson, J. N., Chu, L. W., Yu, K., Andriole, G., Church, T., Stanczyk, F. Z., Koshiol, J., Hsing, A. W. 2013; 8 (12)

    Abstract

    Melatonin, a marker for the circadian rhythm with serum levels peaking between 2AM and 5AM, is hypothesized to possess anti-cancer properties, making it a mechanistic candidate for the probable carcinogenic effect of circadian rhythm disruption. In order to weigh epidemiologic evidence on the association of melatonin with cancer, we must first understand the laboratory and biological sources of variability in melatonin levels measured in samples. Participants for this methodological study were men enrolled in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO). We measured serum melatonin levels over a five year period in 97 individuals to test if melatonin levels are steady over time. The Pearson correlation coefficient between two measures separated by 1 year was 0.87, while the correlation between two measures separated by 5 years was to 0.70. In an additional cross-sectional study of 292 individuals, we used Analysis of Variance to identify differences in melatonin levels between different lifestyle and environmental characteristics. Serum melatonin levels were slightly higher in samples collected from 130 individuals during the winter, (6.36±0.59 pg/ml) than in samples collected from 119 individuals during the summer (4.83±0.62 pg/ml). Serum melatonin levels were lowest in current smokers (3.02±1.25 pg/ml, p = 0.007) compared to never (6.66±0.66 pg/ml) and former (5.59±0.50 pg/ml) smokers whereas BMI did not significantly affect serum melatonin levels in this study. In conclusion, the high 5 year correlation of melatonin levels implies that single measurements may be used to detect population level associations between melatonin and risk of cancer. Furthermore, our results reiterate the need to record season of sample collection, and individual characteristics in order to maximize study power and prevent confounding.

    View details for DOI 10.1371/journal.pone.0083208

    View details for Web of Science ID 000328882000069

    View details for PubMedID 24376664

  • Joint effects between five identified risk variants, allergy, and autoimmune conditions on glioma risk CANCER CAUSES & CONTROL Safaeian, M., Rajaraman, P., Hartge, P., Yeager, M., Linet, M., Butler, M. A., Ruder, A. M., Purdue, M. P., Hsing, A., Beane-Freeman, L., Hoppin, J. A., Albanes, D., Weinstein, S. J., Inskip, P. D., Brenner, A., Rothman, N., Chatterjee, N., Gillanders, E. M., Chanock, S. J., Wang, S. S. 2013; 24 (10): 1885-1891

    Abstract

    Common variants in two of the five genetic regions recently identified from genome-wide association studies (GWAS) of risk of glioma were reported to interact with a history of allergic symptoms. In a pooled analysis of five epidemiologic studies, we evaluated the association between the five GWAS implicated gene variants and allergies and autoimmune conditions (AIC) on glioma risk (851 adult glioma cases and 3,977 controls). We further evaluated the joint effects between allergies and AIC and these gene variants on glioma risk. Risk estimates were calculated as odds ratios (OR) and 95 % confidence intervals (95 % CI), adjusted for age, gender, and study. Joint effects were evaluated by conducting stratified analyses whereby the risk associations (OR and 95 % CI) with the allergy or autoimmune conditions for glioma were evaluated by the presence or absence of the 'at-risk' variant, and estimated p interaction by fitting models with the main effects of allergy or autoimmune conditions and genotype and an interaction (product) term between them. Four of the five SNPs previously reported by others were statistically significantly associated with increased risk of glioma in our study (rs2736100, rs4295627, rs4977756, and rs6010620); rs498872 was not associated with glioma in our study. Reporting any allergies or AIC was associated with reduced risks of glioma (allergy: adjusted OR = 0.71, 95 % CI 0.55-0.91; AIC: adjusted OR = 0.65, 95 % CI 0.47-0.90). We did not observe differential association between allergic or autoimmune conditions and glioma by genotype, and there were no statistically significant p interactions. Stratified analysis by glioma grade (low and high grade) did not suggest risk differences by disease grade. Our results do not provide evidence that allergies or AIC modulate the association between the four GWAS-identified SNPs examined and risk of glioma.

    View details for DOI 10.1007/s10552-013-0244-7

    View details for Web of Science ID 000324252500012

    View details for PubMedID 23903690

  • Biliary tract cancer incidence in the United StatesDemographic and temporal variations by anatomic site INTERNATIONAL JOURNAL OF CANCER Castro, F. A., Koshiol, J., Hsing, A. W., Devesa, S. S. 2013; 133 (7): 1664-1671

    Abstract

    We evaluated incidence patterns of biliary tract cancers (gallbladder, extrahepatic bile duct, ampulla of Vater and not otherwise specified) to provide potential insight into the etiology of these cancers. Data were obtained from the population-based Surveillance, Epidemiology and End Results program. Rates for cases diagnosed during 1992-2009 were calculated by racial/ethnic, gender and age groups. Temporal trends during 1974-2009 and annual percentage changes (APC) during 1992-2009 were estimated. Age-adjusted rates by site were higher among American Indian/Alaska Natives, Hispanics (white) and Asian/Pacific Islanders (Asian/PI) and lower among whites and blacks. Gallbladder cancer was more common among women in all ethnic groups (female-to-male incidence rate ratio [IRR] ranged from 1.24 to 2.86), but bile duct and ampulla of Vater cancers were more common among men (female-to-male IRR 0.57 to 0.82). Gallbladder cancer rates declined among all racial/ethnic and gender groups except blacks (APC -0.4% to -3.9%). In contrast, extrahepatic bile duct cancer rates rose significantly in most female racial/ethnic groups; the APCs among whites were 0.8 among females and 1.3 among males, both significant. Rates for ampulla of Vater cancer decreased among Asian/PI females (APC -2.7%) but remained stable for the other groups. In addition to confirming that biliary tract cancer incidence patterns differ by gender and site and that the gallbladder cancer incidence rates have been declining, our study provides novel evidence that extrahepatic bile duct cancer rates are rising. These observations may help guide future etiologic studies.

    View details for DOI 10.1002/ijc.28161

    View details for Web of Science ID 000321762200015

    View details for PubMedID 23504585

  • Prospective evaluation of serum sarcosine and risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial CARCINOGENESIS Koutros, S., Meyer, T. E., Fox, S. D., Issaq, H. J., Veenstra, T. D., Huang, W., Yu, K., Albanes, D., Chu, L. W., Andriole, G., Hoover, R. N., Hsing, A. W., Berndt, S. I. 2013; 34 (10): 2281-2285

    Abstract

    Metabolomic profiling has identified, sarcosine, a derivative of the amino acid glycine, as an important metabolite involved in the etiology or natural history of prostate cancer. We examined the association between serum sarcosine levels and risk of prostate cancer in 1122 cases (813 non-aggressive and 309 aggressive) and 1112 controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Sarcosine was quantified using high-throughput liquid chromatography-mass spectrometry. A significantly increased risk of prostate cancer was observed with increasing levels of sarcosine (odds ratio [OR] for the highest quartile of exposure [Q4] versus the lowest quartile [Q1] = 1.30, 95% confidence interval [CI]: 1.02, 1.65; P-trend 0.03). When stratified by disease aggressiveness, we observed a stronger association for non-aggressive cases (OR for Q4 versus Q1 = 1.44, 95% CI: 1.11, 1.88; P-trend 0.006) but no association for aggressive prostate cancer (OR for Q4 versus Q1 = 1.03, 95% CI: 0.73, 1.47; P-trend 0.89). Although not statistically significant, temporal analyses showed a stronger association between sarcosine and prostate cancer for serum collected closer to diagnosis, suggesting that sarcosine may be an early biomarker of disease. Interestingly, the association between sarcosine and prostate cancer risk was stronger among men with diabetes (OR = 2.66, 95% CI: 1.04, 6.84) compared with those without reported diabetes (OR = 1.23, 95% CI: 0.95-1.59, P-interaction = 0.01). This study found that elevated levels of serum sarcosine are associated with an increased prostate cancer risk and evidence to suggest that sarcosine may be an early biomarker for this disease.

    View details for DOI 10.1093/carcin/bgt176

    View details for Web of Science ID 000325486200011

    View details for PubMedID 23698636

    View details for PubMedCentralID PMC3786375

  • Variants in CCK and CCKAR genes to susceptibility to biliary tract cancers and stones: A population-based study in Shanghai, China JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Xu, H., Hsing, A. W., Vogtmann, E., Chu, L. W., Cheng, J., Gao, J., Tan, Y., Wang, B., Shen, M., Gao, Y. 2013; 28 (9): 1476-1481

    Abstract

    Altered motility of the gallbladder is associated with an increased risk of gallstones and can result in biliary tract cancers. Cholecystokinin (CCK) is an important modulator of gallbladder motility which functions by activating CCK type-A receptor (CCKAR). The aim of this study was to determine whether genetic variants in CCK and CCKAR are associated with the risk of biliary tract cancers and stones.We investigated the associations between nine single nucleotide polymorphisms in CCK and CCKAR in a population-based case-control study, including 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct, and 53 ampulla of Vater cancer cases), 429 biliary stone cases, and 447 population controls in Shanghai, China.We found that women with the CCKAR rs1800855 AA genotype had an increased risk of gallbladder cancer (odds ratio = 2.37, 95% confidence interval (CI): 1.36-4.14) compared with subjects with the TT genotype, and remained significant after Bonferroni correction (P = 0.0056). Additionally, female carriers of the CCKAR haplotype C-T-C-T (rs2071011-rs915889-rs3822222-rs1800855) had a reduced risk of gallbladder cancer (odds ratio = 0.61, 95% confidence interval: 0.43-0.86) compared with those with the G-C-C-A haplotype; the association also remained significant after Bonferroni correction.These findings suggest that variants in the CCKAR gene may influence the risk of gallbladder cancer in women. Additional studies are needed to confirm our findings.

    View details for DOI 10.1111/jgh.12278

    View details for Web of Science ID 000323389700010

    View details for PubMedID 23701593

    View details for PubMedCentralID PMC3820582

  • Evolution and Taxonomic Classification of Alphapapillomavirus 7 Complete Genomes: HPV18, HPV39, HPV45, HPV59, HPV68 and HPV70 PLOS ONE Chen, Z., Schiffman, M., Herrero, R., DeSalle, R., Anastos, K., Segondy, M., Sahasrabuddhe, V. V., Gravitt, P. E., Hsing, A. W., Burk, R. D. 2013; 8 (8)

    Abstract

    The species Alphapapillomavirus 7 (alpha-7) contains human papillomavirus genotypes that account for 15% of invasive cervical cancers and are disproportionately associated with adenocarcinoma of the cervix. Complete genome analyses enable identification and nomenclature of variant lineages and sublineages.The URR/E6 region was sequenced to screen for novel variants of HPV18, 39, 45, 59, 68, 70, 85 and 97 from 1147 cervical samples obtained from multiple geographic regions that had previously been shown to contain an alpha-7 HPV isolate. To study viral heterogeneity, the complete 8 kb genome of 128 isolates, including 109 sequenced for this analysis, were annotated and analyzed. Viral evolution was characterized by constructing phylogenic trees using maximum-likelihood and Bayesian algorithms. Global and pairwise alignments were used to calculate total and ORF/region nucleotide differences; lineages and sublineages were assigned using an alphanumeric system. The prototype genome was assigned to the A lineage or A1 sublineage.The genomic diversity of alpha-7 HPV types ranged from 1.1% to 6.7% nucleotide sequence differences; the extent of genome-genome pairwise intratype heterogeneity was 1.1% for HPV39, 1.3% for HPV59, 1.5% for HPV45, 1.6% for HPV70, 2.1% for HPV18, and 6.7% for HPV68. ME180 (previously a subtype of HPV68) was designated as the representative genome for HPV68 sublineage C1. Each ORF/region differed in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) / noncoding region 2 (NCR2) > upstream regulatory region (URR) > E6 / E7 > E2 / L2 > E1 / L1.These data provide estimates of the maximum viral genomic heterogeneity of alpha-7 HPV type variants. The proposed taxonomic system facilitates the comparison of variants across epidemiological and molecular studies. Sequence diversity, geographic distribution and phylogenetic topology of this clinically important group of HPVs suggest an independent evolutionary history for each type.

    View details for DOI 10.1371/journal.pone.0072565

    View details for Web of Science ID 000323570200075

    View details for PubMedID 23977318

  • Known glioma risk loci are associated with glioma with a family history of brain tumours - A case-control gene association study INTERNATIONAL JOURNAL OF CANCER Melin, B., Dahlin, A. M., Andersson, U., Wang, Z., Henriksson, R., Hallmans, G., Bondy, M. L., Johansen, C., Feychting, M., Ahlbom, A., Kitahara, C. M., Wang, S. S., Ruder, A. M., Carreon, T., Butler, M. A., Inskip, P. D., Purdue, M., Hsing, A. W., Mechanic, L., Gillanders, E., Yeager, M., Linet, M., Chanock, S. J., Hartge, P., Rajaraman, P. 2013; 132 (10): 2464-2468

    Abstract

    Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.

    View details for DOI 10.1002/ijc.27922

    View details for Web of Science ID 000315512300024

    View details for PubMedID 23115063

  • A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nature genetics Monda, K. L., Chen, G. K., Taylor, K. C., Palmer, C., Edwards, T. L., Lange, L. A., Ng, M. C., Adeyemo, A. A., Allison, M. A., Bielak, L. F., Chen, G., Graff, M., Irvin, M. R., Rhie, S. K., Li, G., Liu, Y., Liu, Y., Lu, Y., Nalls, M. A., Sun, Y. V., Wojczynski, M. K., Yanek, L. R., Aldrich, M. C., Ademola, A., Amos, C. I., Bandera, E. V., Bock, C. H., Britton, A., Broeckel, U., Cai, Q., Caporaso, N. E., Carlson, C. S., Carpten, J., Casey, G., Chen, W., Chen, F., Chen, Y. I., Chiang, C. W., Coetzee, G. A., Demerath, E., Deming-Halverson, S. L., Driver, R. W., Dubbert, P., Feitosa, M. F., Feng, Y., Freedman, B. I., Gillanders, E. M., Gottesman, O., Guo, X., Haritunians, T., Harris, T., Harris, C. C., Hennis, A. J., Hernandez, D. G., McNeill, L. H., Howard, T. D., Howard, B. V., Howard, V. J., Johnson, K. C., Kang, S. J., Keating, B. J., Kolb, S., Kuller, L. H., Kutlar, A., Langefeld, C. D., Lettre, G., Lohman, K., Lotay, V., Lyon, H., Manson, J. E., Maixner, W., Meng, Y. A., Monroe, K. R., Morhason-Bello, I., Murphy, A. B., Mychaleckyj, J. C., Nadukuru, R., Nathanson, K. L., Nayak, U., N'Diaye, A., Nemesure, B., Wu, S., Leske, M. C., Neslund-Dudas, C., Neuhouser, M., Nyante, S., Ochs-Balcom, H., Ogunniyi, A., Ogundiran, T. O., Ojengbede, O., Olopade, O. I., Palmer, J. R., Ruiz-Narvaez, E. A., Palmer, N. D., Press, M. F., Rampersaud, E., Rasmussen-Torvik, L. J., Rodriguez-Gil, J. L., Salako, B., Schadt, E. E., Schwartz, A. G., Shriner, D. A., Siscovick, D., Smith, S. B., Wassertheil-Smoller, S., Speliotes, E. K., Spitz, M. R., Sucheston, L., Taylor, H., Tayo, B. O., Tucker, M. A., Van den Berg, D. J., Edwards, D. R., Wang, Z., Wiencke, J. K., Winkler, T. W., Witte, J. S., Wrensch, M., Wu, X., Yang, J. J., Levin, A. M., Young, T. R., Zakai, N. A., Cushman, M., Zanetti, K. A., Zhao, J. H., Zhao, W., Zheng, Y., Zhou, J., Ziegler, R. G., Zmuda, J. M., Fernandes, J. K., Gilkeson, G. S., Kamen, D. L., Hunt, K. J., Spruill, I. J., Ambrosone, C. B., Ambs, S., Arnett, D. K., Atwood, L., Becker, D. M., Berndt, S. I., Bernstein, L., Blot, W. J., Borecki, I. B., Bottinger, E. P., Bowden, D. W., Burke, G., Chanock, S. J., Cooper, R. S., Ding, J., Duggan, D., Evans, M. K., Fox, C., Garvey, W. T., Bradfield, J. P., Hakonarson, H., Grant, S. F., Hsing, A., Chu, L., Hu, J. J., Huo, D., Ingles, S. A., John, E. M., Jordan, J. M., Kabagambe, E. K., Kardia, S. L., Kittles, R. A., Goodman, P. J., Klein, E. A., Kolonel, L. N., Le Marchand, L., Liu, S., McKnight, B., Millikan, R. C., Mosley, T. H., Padhukasahasram, B., Williams, L. K., Patel, S. R., Peters, U., Pettaway, C. A., Peyser, P. A., Psaty, B. M., Redline, S., Rotimi, C. N., Rybicki, B. A., Sale, M. M., Schreiner, P. J., Signorello, L. B., Singleton, A. B., Stanford, J. L., Strom, S. S., Thun, M. J., Vitolins, M., Zheng, W., Moore, J. H., Williams, S. M., Ketkar, S., Zhu, X., Zonderman, A. B., Kooperberg, C., Papanicolaou, G. J., Henderson, B. E., Reiner, A. P., Hirschhorn, J. N., Loos, R. J., North, K. E., Haiman, C. A. 2013; 45 (6): 690-696

    Abstract

    Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

    View details for DOI 10.1038/ng.2608

    View details for PubMedID 23583978

  • Metabolomics in Epidemiology: Sources of Variability in Metabolite Measurements and Implications CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sampson, J. N., Boca, S. M., Shu, X. O., Stolzenberg-Solomon, R. Z., Matthews, C. E., Hsing, A. W., Tan, Y. T., Ji, B., Chow, W., Cai, Q., Liu, D. K., Yang, G., Xiang, Y. B., Zheng, W., Sinha, R., Cross, A. J., Moore, S. C. 2013; 22 (4): 631-640

    Abstract

    Metabolite levels within an individual vary over time. This within-individual variability, coupled with technical variability, reduces the power for epidemiologic studies to detect associations with disease. Here, the authors assess the variability of a large subset of metabolites and evaluate the implications for epidemiologic studies.Using liquid chromatography/mass spectrometry (LC/MS) and gas chromatography-mass spectroscopy (GC/MS) platforms, 385 metabolites were measured in 60 women at baseline and year-one of the Shanghai Physical Activity Study, and observed patterns were confirmed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening study.Although the authors found high technical reliability (median intraclass correlation = 0.8), reliability over time within an individual was low. Taken together, variability in the assay and variability within the individual accounted for the majority of variability for 64% of metabolites. Given this, a metabolite would need, on average, a relative risk of 3 (comparing upper and lower quartiles of "usual" levels) or 2 (comparing quartiles of observed levels) to be detected in 38%, 74%, and 97% of studies including 500, 1,000, and 5,000 individuals. Age, gender, and fasting status factors, which are often of less interest in epidemiologic studies, were associated with 30%, 67%, and 34% of metabolites, respectively, but the associations were weak and explained only a small proportion of the total metabolite variability.Metabolomics will require large, but feasible, sample sizes to detect the moderate effect sizes typical for epidemiologic studies.We offer guidelines for determining the sample sizes needed to conduct metabolomic studies in epidemiology.

    View details for DOI 10.1158/1055-9965.EPI-12-1109

    View details for Web of Science ID 000317960900020

    View details for PubMedID 23396963

    View details for PubMedCentralID PMC3617076

  • Insulin-Like Growth Factors and Insulin-Like Growth Factor-Binding Proteins and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial CANCER PREVENTION RESEARCH Neuhouser, M. L., Platz, E. A., Till, C., Tangen, C. M., Goodman, P. J., Kristal, A., Parnes, H. L., Tao, Y., Figg, W. D., Lucia, M. S., Hoque, A., Hsing, A. W., Thompson, I. M., Pollak, M. 2013; 6 (2): 91-99

    Abstract

    The role of the insulin-like growth factor (IGF) axis and whether IGFs interact with androgen-suppressing agents in relation to prostate carcinogenesis is unclear. This nested case-control study (n = 1,652 cases/1,543 controls) examined whether serum IGF1, IGF2, IGFBP2, IGFBP3, and the IGF1:IGFBP3 ratio were associated with prostate cancer in the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Baseline serum was assayed for IGF-axis analytes using ELISA. Logistic regression estimated ORs and 95% confidence intervals for risk of total, low-grade (Gleason 2-6) and high-grade (Gleason 7-10) cancers. Results were stratified by intervention assignment. In both the placebo and finasteride arms, serum IGF1, IGF2, IGFBP3, and the IGF1:IGFBP3 ratio were not associated with prostate cancer. However, men in the highest versus lowest quartile of serum IGFBP2 had a 48% (P(trend) = 0.02) and 55% (P(trend) = 0.01) increased risk for total and low-grade cancers, respectively. These IGFBP2 associations were attenuated and no longer statistically significant in the finasteride arm. Our results suggest that in general, serum IGF-axis analytes were not associated with prostate cancer risk in the PCPT in which presence or absence of all cancers was biopsy-determined. The exception was the finding that high serum IGFBP2 is a risk factor for low-grade disease, which was attenuated for men on finasteride. Further research is needed to understand better the risk incurred by high IGFBP2 and whether androgen-suppressing agents such as finasteride influence aspects of IGFBP2 physiology relevant to prostate carcinogenesis.

    View details for DOI 10.1158/1940-6207.CAPR-12-0250

    View details for Web of Science ID 000314676600004

    View details for PubMedID 23315596

  • Global patterns of prostate cancer incidence, aggressiveness, and mortality in men of african descent. Prostate cancer Rebbeck, T. R., Devesa, S. S., Chang, B., Bunker, C. H., Cheng, I., Cooney, K., Eeles, R., Fernandez, P., Giri, V. N., Gueye, S. M., Haiman, C. A., Henderson, B. E., Heyns, C. F., Hu, J. J., Ingles, S. A., Isaacs, W., Jalloh, M., John, E. M., Kibel, A. S., Kidd, L. R., Layne, P., Leach, R. J., Neslund-Dudas, C., Okobia, M. N., Ostrander, E. A., Park, J. Y., Patrick, A. L., Phelan, C. M., Ragin, C., Roberts, R. A., Rybicki, B. A., Stanford, J. L., Strom, S., Thompson, I. M., Witte, J., Xu, J., Yeboah, E., Hsing, A. W., Zeigler-Johnson, C. M. 2013; 2013: 560857-?

    Abstract

    Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

    View details for DOI 10.1155/2013/560857

    View details for PubMedID 23476788

    View details for PubMedCentralID PMC3583061

  • Detectability and reproducibility of plasma levels of chemokines and soluble receptors. Results in immunology Agalliu, I., Xue, X., Cushman, M., Cornell, E., Hsing, A. W., Kaplan, R. C., Anastos, K., Rajpathak, S., Ho, G. Y. 2013; 3: 79-84

    Abstract

    Multiplex assays are available to measure an array of circulating chemokines, soluble cytokine receptors and growth factors. However, there is limited information regarding whether these analytes are suitable for large-scale epidemiological studies to assess their relationships with chronic diseases, including cancer.We examined detectability, assay repeatability, and 3-year within-subject reproducibility of plasma levels of 25 chemokines and 11 soluble receptors of cytokines and growth factors selected from the Human Millipore Panels. Plasma samples were obtained from 36 men (average age 62 years) and 17 women (average age 32 years) who participated in two epidemiological studies. Inter-assay and within-subject reproducibility were assessed by intraclass correlation coefficients (ICC).All analytes, except lymphotactin (47% detectability), were detectable in >90% of plasma samples. Inter-assay reproducibility for all analytes in 36 men tested three times on separate days were good to excellent (ICCs: 0.71-1.00). Within-subject reproducibility in 17 women sampled three times in three years were excellent (ICC ≥ 0.75) for five chemokines (eotaxin, fractalkine, 6Ckine, eotaxin 3, and SDF-1α+β) and three soluble receptors (sIL-1R2, sIL-4R and sVEGFR2); ICCs were fair to good (0.4 ≤ ICC < 0.75) for 15 chemokines and eight soluble receptors. However, five chemokines (GRO, IP-10, MIP-1β, BCA-1, and MIP-3α) had ICC < 0.4, suggesting biological variability.Multiplex assays for plasma levels of selected chemokines and soluble receptors showed good to excellent assay detectability and repeatability. Most analytes also had good 3-year within-subject reproducibility, indicating that a single measurement of these analytes may be used to assess biomarker-disease associations.

    View details for DOI 10.1016/j.rinim.2013.07.001

    View details for PubMedID 24600562

  • Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 NATURE GENETICS Xu, J., Mo, Z., Ye, D., Wang, M., Liu, F., Jin, G., Xu, C., Wang, X., Shao, Q., Chen, Z., Tao, Z., Qi, J., Zhou, F., Wang, Z., Fu, Y., He, D., Wei, Q., Guo, J., Wu, D., Gao, X., Yuan, J., Wang, G., Xu, Y., Wang, G., Yao, H., Dong, P., Jiao, Y., Shen, M., Yang, J., Jun Ou-Yang, O. Y., Jiang, H., Zhu, Y., Ren, S., Zhang, Z., Yin, C., Gao, X., Dai, B., Hu, Z., Yang, Y., Wu, Q., Chen, H., Peng, P., Zheng, Y., Zheng, X., Xiang, Y., Long, J., Gong, J., Na, R., Lin, X., Yu, H., Wang, Z., Tao, S., Feng, J., Sun, J., Liu, W., Hsing, A., Rao, J., Ding, Q., Wiklund, F., Gronberg, H., Shu, X., Zheng, W., Shen, H., Jin, L., Shi, R., Lu, D., Zhang, X., Sun, J., Zheng, S. L., Sun, Y. 2012; 44 (11): 1231-1235

    Abstract

    Prostate cancer risk-associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk-associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10(-14)) and 19q13.4 (rs103294, P = 5.34 × 10(-16)) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10(-4)). These findings may advance the understanding of genetic susceptibility to prostate cancer.

    View details for DOI 10.1038/ng.2424

    View details for Web of Science ID 000310495800015

    View details for PubMedID 23023329

  • Associations of serum sex steroid hormone and 5a-androstane-3a,17ß-diol glucuronide concentrations with prostate cancer risk among men treated with finasteride. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Kristal, A. R., Till, C., Tangen, C. M., Goodman, P. J., Neuhouser, M. L., Stanczyk, F. Z., Chu, L. W., Patel, S. K., Thompson, I. M., Reichardt, J. K., Hoque, A., Platz, E. A., Figg, W. D., van Bokhoven, A., Lippman, S. M., Hsing, A. W. 2012; 21 (10): 1823-1832

    Abstract

    Finasteride, an inhibitor of 5α-reductase (type II), lowers intraprostatic dihydrotestosterone (DHT), which is reflected in serum as reduced 5α-androstane-3α,17β-diol glucuronide (3α-dG). It also modestly increases serum testosterone (T), estrone (E(1)), and estradiol (E(2)). In this altered hormonal milieu, it is unknown whether serum concentrations of these hormones are associated with prostate cancer risk.In this nested case-control study of men in the finasteride arm of the Prostate Cancer Prevention Trial, sex steroid hormones and sex hormone binding globulin were measured at baseline and approximately 3-year posttreatment in 553 prostate cancer cases and 694 controls.Median posttreatment changes in concentrations of 3α-dG, T, E(1), and E(2) were -73.8%, +10.1%, +11.2%, and +7.5% (all P < 0.001), respectively. Neither the pre- nor posttreatment concentrations of 3α-dG, nor its change, were associated with risk. Pretreatment, high concentrations of E(1) and low concentrations of T were associated with increased cancer risk [OR; 95% confidence interval (CI) quartile 4 vs. 1: 1.38 (0.99-1.93) P(trend) = 0.03; 0.64 (0.43-0.93) P(trend) = 0.07, respectively]. Posttreatment, high concentrations of both E(1) and E(2) were associated with increased cancer risk [OR; 95% CI quartile 4 vs. 1: 1.54 (1.09-2.17) P(trend) = 0.03; 1.49 (1.07-2.07) P(trend) = 0.02, respectively].Among finasteride-treated men, concentrations of 3α-dG were not associated with total or Gleason grades 2 to 6, 7 to 10, or 8 to 10 cancer. High serum estrogens may increase cancer risk when intraprostatic DHT is pharmacologically lowered.Low posttreatment serum estrogens may identify men more likely to benefit from use of finasteride to prevent prostate cancer.

    View details for DOI 10.1158/1055-9965.EPI-12-0695

    View details for PubMedID 22879203

  • Non-steroidal anti-inflammatory drug use and the risk of benign prostatic hyperplasia-related outcomes and nocturia in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial BJU INTERNATIONAL Sutcliffe, S., Grubb, R. L., Platz, E. A., Ragard, L. R., Riley, T. L., Kazin, S. S., Hayes, R. B., Hsing, A. W., Andriole, G. L. 2012; 110 (7): 1050-1059
  • Associations of Serum Sex Steroid Hormone and 5 alpha-Androstane-3 alpha, 17 beta-Diol Glucuronide Concentrations with Prostate Cancer Risk Among Men Treated with Finasteride CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kristal, A. R., Till, C., Tangen, C. M., Goodman, P. J., Neuhouser, M. L., Stanczyk, F. Z., Chu, L. W., Patel, S. K., Thompson, I. M., Reichardt, J. K., Hoque, A., Platz, E. A., Figg, W. D., van Bokhoven, A., Lippman, S. M., Hsing, A. W. 2012; 21 (10): 1823-1832
  • Ovarian cancer and smoking: individual participant meta-analysis including 28 114 women with ovarian cancer from 51 epidemiological studies LANCET ONCOLOGY Beral, V., Gaitskell, K., Hermon, C., Moser, K., Reeves, G., Peto, R., Brinton, L., Marchbanks, P., Negri, E., Ness, R., Peeters, P. H., Vessey, M., Calle, E. E., Gapstur, S. M., Patel, A. V., Dal Maso, L., Talamini, R., Chetrit, A., Hirsh-Yechezkel, G., Lubin, F., Sadetzki, S., Banks, E., Beral, V., Bull, D., Callaghan, K., Crossley, B., Gaitskell, K., Goodill, A., Green, J., Hermon, C., Key, T., Moser, K., Reeves, G., Sitas, F., Collins, R., DOLL, R., Peto, R., Gonzalez, A., Lee, N., Marchbanks, P., Ory, H. W., Peterson, H. B., Wingo, P. A., Martin, N., PARDTHAISONG, T., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., Tjonneland, A., Titus-Ernstoff, L., Byers, T., Rohan, T., Mosgaard, B. J., Vessey, M., Yeates, D., Freudenheim, J. L., Chang-Claude, J., Kaaks, R., Anderson, K. E., Folsom, A., Robien, K., Hampton, J., Newcomb, P. A., Rossing, M. A., Thomas, D. B., Weiss, N. S., Riboli, E., Clavel-Chapelon, F., Cramer, D., Hankinson, S. E., Tworoger, S. S., Franceschi, S., La Vecchia, C., Negri, E., Adami, H. O., Magnusson, C., Riman, T., Weiderpass, E., Wolk, A., Schouten, L. J., van den Brandt, P. A., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Palli, D., Black, A., Brinton, L. A., Freedman, D. M., Hartge, P., Hsing, A. W., Lacey, J. V., HOOVER, R. N., Schairer, C., Urban, M., Graff-Iversen, S., Selmer, R., Bain, C. J., Green, A. C., Purdie, D. M., Siskind, V., Webb, P. M., Moysich, K., McCann, S. E., Hannaford, P., Kay, C., Binns, C. W., Lee, A. H., Zhang, M., Ness, R. B., Nasca, P., Coogan, P. F., Palmer, J. R., Rosenberg, L., Kelsey, J., Paffenbarger, R., Whittemore, A., Katsouyanni, K., Trichopoulou, A., Trichopoulos, D., Tzonou, A., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Goodman, M. T., Lurie, G., Carney, M. E., Wilkens, L. R., Hartman, L., Manjer, J., Olsson, H., Grisso, J. A., Morgan, M., Wheeler, J. E., Bunker, C. H., Edwards, R. P., Modugno, F., Peeters, P. H., Casagrande, J., Pike, M. C., Ross, R. K., Wu, A. H., Miller, A. B., Kumle, M., Gram, I. T., Lund, E., McGowan, L., Shu, X. O., Zheng, W., Farley, T. M., Holck, S., MEIRIK, O., Risch, H. A. 2012; 13 (9): 946-956

    Abstract

    Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence.Eligible epidemiological studies were identified by electronic searches, review articles, and discussions with colleagues. Individual participant data for 28,114 women with and 94,942 without ovarian cancer from 51 epidemiological studies were analysed centrally, yielding adjusted relative risks (RRs) of ovarian cancer in smokers compared with never smokers.After exclusion of studies with hospital controls, in which smoking could have affected recruitment, overall ovarian cancer incidence was only slightly increased in current smokers compared with women who had never smoked (RR 1·06, 95% CI 1·01-1·11, p=0·01). Of 17,641 epithelial cancers with specified histology, 2314 (13%) were mucinous, 2360 (13%) endometrioid, 969 (5%) clear-cell, and 9086 (52%) serous. Smoking-related risks varied substantially across these subtypes (p(heterogeneity)<0·0001). For mucinous cancers, incidence was increased in current versus never smokers (1·79, 95% CI 1·60-2·00, p<0·0001), but the increase was mainly in borderline malignant rather than in fully malignant tumours (2·25, 95% CI 1·91-2·65 vs 1·49, 1·28-1·73; p(heterogeneity)=0·01; almost half the mucinous tumours were only borderline malignant). Both endometrioid (0·81, 95% CI 0·72-0·92, p=0·001) and clear-cell ovarian cancer risks (0·80, 95% CI 0·65-0·97, p=0·03) were reduced in current smokers, and there was no significant association for serous ovarian cancers (0·99, 95% CI 0·93-1·06, p=0·8). These associations did not vary significantly by 13 sociodemographic and personal characteristics of women including their body-mass index, parity, and use of alcohol, oral contraceptives, and menopausal hormone therapy.The excess of mucinous ovarian cancers in smokers, which is mainly of tumours of borderline malignancy, is roughly counterbalanced by the deficit of endometrioid and clear-cell ovarian cancers. The substantial variation in smoking-related risks by tumour subtype is important for understanding ovarian carcinogenesis.Cancer Research UK and MRC.

    View details for DOI 10.1016/S1470-2045(12)70322-4

    View details for Web of Science ID 000308425600022

    View details for PubMedID 22863523

    View details for PubMedCentralID PMC3431503

  • Prospective study of cytomegalovirus serostatus and prostate cancer risk in the Prostate Cancer Prevention Trial CANCER CAUSES & CONTROL Sutcliffe, S., Till, C., Gaydos, C. A., Jenkins, F. J., Goodman, P. J., Hoque, A. M., Hsing, A. W., Thompson, I. M., Zenilman, J. M., Nelson, W. G., De Marzo, A. M., Platz, E. A. 2012; 23 (9): 1511-1518

    Abstract

    To investigate serologic evidence of infection by cytomegalovirus (CMV), a herpesvirus with known oncogenic potential that has been detected in malignant prostate tissue, in relation to prostate cancer (PCa) risk in a large case-control study nested in the Prostate Cancer Prevention Trial (PCPT).Cases were men with a confirmed diagnosis of PCa after visit 2 (n = 614), and controls were men not diagnosed with PCa during the trial who also had a negative end-of-study biopsy (n = 616). Controls were frequency-matched to cases by age, treatment arm, and family history of PCa. Sera from visit 2 were tested for CMV IgG antibodies.No association was observed between CMV serostatus and PCa risk (adjusted CMV seroprevalence = 67.9 % for cases and 65.2 % for controls, odds ratio = 1.13, 95 % CI 0.89-1.45).Considering our null findings in the context of the full CMV literature, CMV infection, as measured by serostatus, does not appear to increase PCa risk.

    View details for DOI 10.1007/s10552-012-0028-5

    View details for Web of Science ID 000307401400011

    View details for PubMedID 22810146

    View details for PubMedCentralID PMC3433040

  • Association between adult height, genetic susceptibility and risk of glioma INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Kitahara, C. M., Wang, S. S., Melin, B. S., Wang, Z., Braganza, M., Inskip, P. D., Albanes, D., Andersson, U., Freeman, L. E., Buring, J. E., Carreon, T., Feychting, M., Gapstur, S. M., Gaziano, J. M., Giles, G. G., Hallmans, G., Hankinson, S. E., Henriksson, R., Hsing, A. W., Johansen, C., Linet, M. S., McKean-Cowdin, R., Michaud, D. S., Peters, U., Purdue, M. P., Rothman, N., Ruder, A. M., Sesso, H. D., Severi, G., Shu, X., Stevens, V. L., Visvanathan, K., Waters, M. A., White, E., Wolk, A., Zeleniuch-Jacquotte, A., Zheng, W., Hoover, R., Fraumeni, J. F., Chatterjee, N., Yeager, M., Chanock, S. J., Hartge, P., Rajaraman, P. 2012; 41 (4): 1075-1085

    View details for DOI 10.1093/ije/dys114

    View details for Web of Science ID 000308232200026

  • Aspirin but not ibuprofen use is associated with reduced risk of prostate cancer: a PLCO Study BRITISH JOURNAL OF CANCER Shebl, F. M., Sakoda, L. C., Black, A., Koshiol, J., Andriole, G. L., Grubb, R., Church, T. R., Chia, D., Zhou, C., Chu, L. W., Huang, W., Peters, U., Kirsh, V. A., Chatterjee, N., Leitzmann, M. F., Hayes, R. B., Hsing, A. W. 2012; 107 (1): 207-214

    Abstract

    Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear.We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55-74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified.After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with <1 and ≥ 1 pill of aspirin daily were 0.98 (95% confidence interval (CI), 0.90-1.07) and 0.92 (95% CI: 0.85-0.99), respectively, compared with never use (P for trend 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 or men who had a history of cardiovascular-related diseases or arthritis (HR (95% CI); 0.87 (0.78-0.97), 0.89 (0.80-0.99), and 0.88 (0.78-1.00), respectively). The data did not support an association between ibuprofen use and prostate cancer risk.Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer risk.

    View details for DOI 10.1038/bjc.2012.227

    View details for Web of Science ID 000305888400032

    View details for PubMedID 22722313

  • Detectable clonal mosaicism and its relationship to aging and cancer NATURE GENETICS Jacobs, K. B., Yeager, M., Zhou, W., Wacholder, S., Wang, Z., Rodriguez-Santiago, B., Hutchinson, A., Deng, X., Liu, C., Horner, M., Cullen, M., Epstein, C. G., Burdett, L., Dean, M. C., Chatterjee, N., Sampson, J., Chung, C. C., Kovaks, J., Gapstur, S. M., Stevens, V. L., Teras, L. T., Gaudet, M. M., Albanes, D., Weinstein, S. J., Virtamo, J., Taylor, P. R., Freedman, N. D., Abnet, C. C., Goldstein, A. M., Hu, N., Yu, K., Yuan, J., Liao, L., Ding, T., Qiao, Y., Gao, Y., Koh, W., Xiang, Y., Tang, Z., Fan, J., Aldrich, M. C., Amos, C., Blot, W. J., Bock, C. H., Gillanders, E. M., Harris, C. C., Haiman, C. A., Henderson, B. E., Kolonel, L. N., Le Marchand, L., McNeill, L. H., Rybicki, B. A., Schwartz, A. G., Signorello, L. B., Spitz, M. R., Wiencke, J. K., Wrensch, M., Wu, X., Zanetti, K. A., Ziegler, R. G., Figueroa, J. D., Garcia-Closas, M., Malats, N., Marenne, G., Prokunina-Olsson, L., Baris, D., Schwenn, M., Johnson, A., Landi, M. T., Goldin, L., Consonni, D., Bertazzi, P. A., Rotunno, M., Rajaraman, P., Andersson, U., Freeman, L. E., Berg, C. D., Buring, J. E., Butler, M. A., Carreon, T., Feychting, M., Ahlbom, A., Gaziano, J. M., Giles, G. G., Hallmans, G., Hankinson, S. E., Hartge, P., Henriksson, R., Inskip, P. D., Johansen, C., Landgren, A., McKean-Cowdin, R., Michaud, D. S., Melin, B. S., Peters, U., Ruder, A. M., Sesso, H. D., Severi, G., Shu, X., Visvanathan, K., White, E., Wolk, A., Zeleniuch-Jacquotte, A., Zheng, W., Silverman, D. T., Kogevinas, M., Gonzalez, J. R., Villa, O., Li, D., Duell, E. J., Risch, H. A., Olson, S. H., Kooperberg, C., Wolpin, B. M., Jiao, L., Hassan, M., Wheeler, W., Arslan, A. A., Bueno-de-Mesquita, H. B., Fuchs, C. S., Gallinger, S., Gross, M. D., Holly, E. A., Klein, A. P., LaCroix, A., Mandelson, M. T., Petersen, G., Boutron-Ruault, M., Bracci, P. M., Canzian, F., Chang, K., Cotterchio, M., Giovannucci, E. L., Goggins, M., Bolton, J. A., Jenab, M., Khaw, K., Krogh, V., Kurtz, R. C., Mcwilliams, R. R., Mendelsohn, J. B., Rabe, K. G., Riboli, E., Tjonneland, A., Tobias, G. S., Trichopoulos, D., Elena, J. W., Yu, H., Amundadottir, L., Stolzenberg-Solomon, R. Z., Kraft, P., Schumacher, F., Stram, D., Savage, S. A., Mirabello, L., Andrulis, I. L., Wunder, J. S., Patino Garcia, A., Sierrasesumaga, L., Barkauskas, D. A., Gorlick, R. G., Purdue, M., Chow, W., Moore, L. E., Schwartz, K. L., Davis, F. G., Hsing, A. W., Berndt, S. I., Black, A., Wentzensen, N., Brinton, L. A., Lissowska, J., Peplonska, B., McGlynn, K. A., Cook, M. B., Graubard, B. I., Kratz, C. P., Greene, M. H., Erickson, R. L., Hunter, D. J., Thomas, G., Hoover, R. N., Real, F. X., Fraumeni, J. F., Caporaso, N. E., Tucker, M., Rothman, N., Perez-Jurado, L. A., Chanock, S. J. 2012; 44 (6): 651-U68

    Abstract

    In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

    View details for DOI 10.1038/ng.2270

    View details for Web of Science ID 000304551100011

    View details for PubMedID 22561519

  • Prevalence of BPH and lower urinary tract symptoms in West Africans PROSTATE CANCER AND PROSTATIC DISEASES Chokkalingam, A. P., YEBOAH, E. D., DeMarzo, A., Netto, G., Yu, K., Biritwum, R. B., Tettey, Y., Adjei, A., Jadallah, S., Li, Y., Chu, L. W., Chia, D., Niwa, S., Partin, A., THOMPSON, I. M., Roehrborn, C., HOOVER, R. N., Hsing, A. W. 2012; 15 (2): 170-176

    Abstract

    BPH and lower urinary tract symptoms (LUTS) are very common among older men in Western countries. However, the prevalence of these two conditions in the developing countries is less clear.We assessed the age-standardized prevalence of BPH and/or LUTS among West Africans in a probability sample of 950 men aged 50-74 in Accra, Ghana, with no evidence of biopsy-confirmed prostate cancer after screening with PSA and digital rectal examination (DRE). Information on LUTS was based on self-reports of the International Prostate Symptom Score (IPSS). BPH was estimated using DRE, PSA levels and imputed prostate volume.The prevalence of DRE-detected enlarged prostate was 62.3%, while that of PSA≥1.5 ng ml(-1) (an estimate of prostate volume ≥ 30 cm(3)) was 35.3%. The prevalence of moderate-to-severe LUTS (IPSS≥8) was 19.9%. The prevalence of IPSS≥8 and an enlarged prostate on DRE was 13.3%. Although there is no universally agreed-upon definition of BPH/LUTS, making comparisons across populations difficult, BPH and/or LUTS appear to be quite common among older Ghanaian men.We found that after age standardization, the prevalence of DRE-detected enlarged prostate in Ghanaian men is higher than previously reported for American men, but the prevalence of LUTS was lower than previously reported for African Americans. Further studies are needed to confirm these findings and identify the risk factors for BPH in both Africans and African Americans.

    View details for DOI 10.1038/pcan.2011.43

    View details for Web of Science ID 000304044300009

    View details for PubMedID 21912428

  • Interactions Between Genome-wide Significant Genetic Variants and Circulating Concentrations of Insulin-like Growth Factor 1, Sex Hormones, and Binding Proteins in Relation to Prostate Cancer Risk in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium AMERICAN JOURNAL OF EPIDEMIOLOGY Tsilidis, K. K., Travis, R. C., Appleby, P. N., Allen, N. E., Lindstrom, S., Schumacher, F. R., Cox, D., Hsing, A. W., Ma, J., Severi, G., Albanes, D., Virtamo, J., Boeing, H., Bueno-de-Mesquita, H. B., Johansson, M., Ramon Quiros, J., Riboli, E., Siddiq, A., Tjonneland, A., Trichopoulos, D., Tumino, R., Gaziano, J. M., Giovannucci, E., Hunter, D. J., Kraft, P., Stampfer, M. J., Giles, G. G., Andriole, G. L., Berndt, S. I., Chanock, S. J., Hayes, R. B., Key, T. J. 2012; 175 (9): 926-935

    Abstract

    Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. There is limited information on the mechanistic basis of these associations, particularly about whether they interact with circulating concentrations of growth factors and sex hormones, which may be important in prostate cancer etiology. Using conditional logistic regression, the authors compared per-allele odds ratios for prostate cancer for 39 GWAS-identified SNPs across thirds (tertile groups) of circulating concentrations of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), testosterone, androstenedione, androstanediol glucuronide, estradiol, and sex hormone-binding globulin (SHBG) for 3,043 cases and 3,478 controls in the Breast and Prostate Cancer Cohort Consortium. After allowing for multiple testing, none of the SNPs examined were significantly associated with growth factor or hormone concentrations, and the SNP-prostate cancer associations did not differ by these concentrations, although 4 interactions were marginally significant (MSMB-rs10993994 with androstenedione (uncorrected P = 0.008); CTBP2-rs4962416 with IGFBP-3 (uncorrected P = 0.003); 11q13.2-rs12418451 with IGF-1 (uncorrected P = 0.006); and 11q13.2-rs10896449 with SHBG (uncorrected P = 0.005)). The authors found no strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of IGF-1, sex hormones, or their major binding proteins.

    View details for DOI 10.1093/aje/kwr423

    View details for Web of Science ID 000303653000010

    View details for PubMedID 22459122

  • Ovarian Cancer and Body Size: Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies PLOS MEDICINE Beral, V., Hermon, C., Peto, R., Reeves, G., Brinton, L., Marchbanks, P., Negri, E., Ness, R., Peeters, P. H., Vessey, M., Calle, E. E., Gapstur, S. M., Patel, A. V., Dal Maso, L., Talamini, R., Chetrit, A., Hirsh-Yechezkel, G., Lubin, F., Sadetzki, S., Allen, N., Bull, D., Callaghan, K., Crossley, B., Gaitskell, K., Goodill, A., Green, J., Key, T., Moser, K., Collins, R., DOLL, R., Gonzalez, C. A., Lee, N., Ory, H. W., Peterson, H. B., Wingo, P. A., Martin, N., PARDTHAISONG, T., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., Tjonneland, A., Titus-Ernstoff, L., Byers, T., Rohan, T., Mosgaard, B. J., Yeates, D., Freudenheim, J. L., Chang-Claude, J., Kaaks, R., Anderson, K. E., Folsom, A., Robien, K., Rossing, M. A., Thomas, D. B., Weiss, N. S., Riboli, E., Clavel-Chapelon, F., Cramer, D., Hankinson, S. E., Tworoger, S. S., Franceschi, S., La Vecchia, C., Magnusson, C., Riman, T., Weiderpass, E., Wolk, A., Schouten, L. J., van den Brandt, P. A., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Palli, D., Black, A., de Gonzalez, A. B., Freedman, D. M., Hartge, P., Hsing, A. W., Lacey, J. V., HOOVER, R. N., Schairer, C., Graff-Iversen, S., Selmer, R., Bain, C. J., Green, A. C., Purdie, D. M., Siskind, V., Webb, P. M., McCann, S. E., Hannaford, P., Kay, C., Binns, C. W., Lee, A. H., Zhang, M., Ness, R. B., Nasca, P., Coogan, P. F., Palmer, J. R., Rosenberg, L., Kelsey, J., Paffenbarger, R., Whittemore, A., Katsouyanni, K., Trichopoulou, A., Trichopoulos, D., Tzonou, A., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Goodman, M. T., Lurie, G., Carney, M. E., Wilkens, L. R., Hartman, L., Manjer, J., Olsson, H., Grisso, J. A., Morgan, M., Wheeler, J. E., Casagrande, J., Pike, M. C., Ross, R. K., Wu, A. H., Miller, A. B., Kumle, M., Lund, E., McGowan, L., Shu, X. O., Zheng, W., Farley, T. M., Holck, S., MEIRIK, O., Risch, H. A. 2012; 9 (4)

    Abstract

    Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships.Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index. Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05-1.09; p<0.001); this relationship did not vary significantly by women's age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m(2) increase in body mass index was 1.10 (95% CI, 1.07-1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92-0.99; p=0.02) in ever-users of hormone therapy.Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade. Please see later in the article for the Editors' Summary.

    View details for DOI 10.1371/journal.pmed.1001200

    View details for Web of Science ID 000303393800003

    View details for PubMedID 22606070

    View details for PubMedCentralID PMC3317899

  • Predictive Performance of prostate cancer risk in Chinese men using 33 reported prostate cancer risk-associated SNPs PROSTATE Zheng, J., Liu, F., Lin, X., Wang, X., Ding, Q., Jiang, H., Chen, H., Lu, D., Jin, G., Hsing, A. W., Shao, Q., Qi, J., Ye, Y., Wang, Z., Gao, X., Wang, G., Chu, L. W., Ouyang, J., Huang, Y., Chen, Y., Gao, Y., Shi, R., Wu, Q., Wang, M., Zhang, Z., Hu, Y., Sun, J., Zheng, S. L., Gao, X., Xu, C., Mo, Z., Sun, Y., Xu, J. 2012; 72 (5): 577-583

    Abstract

    Genome-wide association studies (GWAS) have identified more than 30 single nucleotide polymorphisms (SNPs) that were reproducibly associated with prostate cancer (PCa) risk in populations of European descent. In aggregate, these variants have shown potential to predict risk for PCa in European men. However, their utility for PCa risk prediction in Chinese men is unknown.We selected 33 PCa risk-related SNPs that were originally identified in populations of European descent. Genetic scores were estimated for subjects in a Chinese case-control study (1,108 cases and 1,525 controls) based on these SNPs. To assess the performance of the genetic score on its ability to predict risk for PCa, we calculated area under the curve (AUC) of the receiver operating characteristic (ROC) in combination with 10-fold cross-validation.The genetic score was significantly higher for cases than controls (P = 5.91 × 10(-20)), and was significantly associated with risk of PCa in a dose-dependent manner (P for trend: 4.78 × 10(-18)). The AUC of the genetic score was 0.604 for risk prediction of PCa in Chinese men. When ORs derived from this Chinese study population were used to calculate genetic score, the AUCs were 0.631 for all 33 SNPs and 0.617 when using only the 11 significant SNPs.Our results indicate that genetic variants related to PCa risk may be useful for risk prediction in Chinese men. Prospective studies are warranted to further evaluate these findings.

    View details for DOI 10.1002/pros.21462

    View details for Web of Science ID 000300703000013

    View details for PubMedID 21796652

    View details for PubMedCentralID PMC3232337

  • Physical activity, diabetes, and thyroid cancer risk: a pooled analysis of five prospective studies CANCER CAUSES & CONTROL Kitahara, C. M., Platz, E. A., Freeman, L. E., Black, A., Hsing, A. W., Linet, M. S., Park, Y., Schairer, C., de Gonzalez, A. B. 2012; 23 (3): 463-471

    Abstract

    PURPOSE: Although many studies have linked obesity with increased risk of thyroid cancer, few have investigated the role of obesity-related lifestyle characteristics and medical conditions in the etiology of this disease. We examined the associations of self-reported physical activity and diabetes history with thyroid cancer risk in a large pooled analysis of prospective cohort studies. METHODS: Data from five prospective studies in the U.S. (n = 362,342 men, 312,149 women) were coded using standardized exposure, covariate, and outcome definitions. Hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer were estimated using age as the time metric and adjusting for sex, education, race, marital status, cigarette smoking, body mass index, alcohol intake, and cohort. Effect modification by other risk factors (e.g., age, sex, and body mass index) and differences by cancer subtype (e.g., papillary, follicular) were also examined. RESULTS: Over follow-up (median = 10.5 years), 308 men and 510 women were diagnosed with a first primary thyroid cancer. Overall, subjects reporting the greatest amount of physical activity had an increased risk of the disease (HR = 1.18, 95% CI:1.00-1.39); however, this association was restricted to participants who were overweight/obese (≥25 kg/m(2); HR = 1.34, 95% CI:1.09-1.64) as opposed to normal-weight (<25 kg/m(2); HR = 0.92, 95% CI:0.69-1.22; P-interaction = 0.03). We found no overall association between self-reported history of diabetes and thyroid cancer risk (HR = 1.08, 95% CI:0.83-1.40). CONCLUSION: Neither physical inactivity nor diabetes history was associated with increased risk of thyroid cancer. While it may have been a chance finding, the possible increased risk associated with greater physical activity warrants further investigation.

    View details for DOI 10.1007/s10552-012-9896-y

    View details for Web of Science ID 000300891100007

    View details for PubMedID 22294499

    View details for PubMedCentralID PMC3586378

  • Replication and cumulative effects of GWAS-identified genetic variations for prostate cancer in Asians: a case-control study in the ChinaPCa consortium CARCINOGENESIS Wang, M., Liu, F., Hsing, A. W., Wang, X., Shao, Q., Qi, J., Ye, Y., Wang, Z., Chen, H., Gao, X., Wang, G., Chu, L. W., Ding, Q., Ouyang, J., Gao, X., Huang, Y., Chen, Y., Gao, Y., Zhang, Z., Rao, J., Shi, R., Wu, Q., Zhang, Y., Jiang, H., Zheng, J., Hu, Y., Guo, L., Lin, X., Tao, S., Jin, G., Sun, J., Lu, D., Zheng, S. L., Sun, Y., Mo, Z., Yin, C., Zhang, Z., Xu, J. 2012; 33 (2): 356-360

    Abstract

    A recent genome-wide association study has identified five new genetic variants for prostate cancer susceptibility in a Japanese population, but it is unknown whether these newly identified variants are associated with prostate cancer risk in other populations, including Chinese men. We genotyped these five variants in a case-control study of 1524 patients diagnosed with prostate cancer and 2169 control subjects from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). We found that three of the five genetic variants were associated with prostate cancer risk (P = 4.33 × 10(-8) for rs12653946 at 5p15, 4.43 × 10(-5) for rs339331 at 6q22 and 8.42 × 10(-4) for rs9600079 at 13q22, respectively). A cumulative effect was observed in a dose-dependent manner with increasing numbers of risk variant alleles (P(trend) = 2.58 × 10(-13)), and men with 5-6 risk alleles had a 2-fold higher risk of prostate cancer than men with 0-2 risk alleles (odds ratio = 2.26, 95% confidence interval = 1.78-2.87). Furthermore, rs339331 T allele was significantly associated with RFX6 and GPRC6A higher messenger RNA expression, compared with the C allele. However, none of the variants was associated with clinical stage, Gleason score or family history. These results provide further evidence that the risk loci identified in Japanese men also contribute to prostate cancer susceptibility in Chinese men.

    View details for DOI 10.1093/carcin/bgr279

    View details for Web of Science ID 000300039800016

    View details for PubMedID 22114074

    View details for PubMedCentralID PMC3271266

  • A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23 HUMAN MOLECULAR GENETICS Wu, X., Scelo, G., Purdue, M. P., Rothman, N., Johansson, M., Ye, Y., Wang, Z., Zelenika, D., Moore, L. E., Wood, C. G., Prokhortchouk, E., Gaborieau, V., Jacobs, K. B., Chow, W., Toro, J. R., Zaridze, D., Lin, J., Lubinski, J., Trubicka, J., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Jinga, V., Bencko, V., Slamova, A., Holcatova, I., Navratilova, M., Janout, V., Boffetta, P., Colt, J. S., Davis, F. G., Schwartz, K. L., Banks, R. E., Selby, P. J., Harnden, P., Berg, C. D., Hsing, A. W., Grubb, R. L., Boeing, H., Vineis, P., Clavel-Chapelon, F., Palli, D., Tumino, R., Krogh, V., Panico, S., Duell, E. J., Ramon Quiros, J., Sanchez, M., Navarro, C., Ardanaz, E., Dorronsoro, M., Khaw, K., Allen, N. E., Bueno-de-Mesquita, H. B., Peeters, P. H., Trichopoulos, D., Linseisen, J., Ljungberg, B., Overvad, K., Tjonneland, A., Romieu, I., Riboli, E., Stevens, V. L., Thun, M. J., Diver, W. R., Gapstur, S. M., Pharoah, P. D., Easton, D. F., Albanes, D., Virtamo, J., Vatten, L., Hveem, K., Fletcher, T., Koppova, K., Cussenot, O., Cancel-Tassin, G., Benhamou, S., Hildebrandt, M. A., Pu, X., Foglio, M., Lechner, D., Hutchinson, A., Yeager, M., Fraumeni, J. F., Lathrop, M., Skryabin, K. G., McKay, J. D., Gu, J., Brennan, P., Chanock, S. J. 2012; 21 (2): 456-462

    Abstract

    Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D ' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.

    View details for DOI 10.1093/hmg/ddr479

    View details for Web of Science ID 000298658300019

    View details for PubMedID 22010048

  • The association between inflammation-related genes and serum androgen levels in men: The prostate, lung, colorectal, and ovarian study PROSTATE Meyer, T. E., Chu, L. W., Li, Q., Yu, K., Rosenberg, P. S., Menashe, I., Chokkalingam, A. P., Quraishi, S. M., Huang, W., Weiss, J. M., Kaaks, R., Hayes, R. B., Chanock, S. J., Hsing, A. W. 2012; 72 (1): 65-71

    Abstract

    Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes.In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5α-androstane-3α, 17β-diol glucuronide [3αdiol G], and 4-androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based P values were generated using an adaptive rank truncated product (ARTP) method.Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-value <0.1) in both SNP and gene-based tests. Specifically, T was associated with common variants in MMP2 and CD14, with the most significant SNPs being rs893226G > T in MMP2 and rs3822356T > C in CD14 (FDR q-value = 0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione.These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk.

    View details for DOI 10.1002/pros.21407

    View details for Web of Science ID 000298588900008

    View details for PubMedID 21520164

    View details for PubMedCentralID PMC3156884

  • Replication of Five Prostate Cancer Loci Identified in an Asian Population-Results from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lindstroem, S., Schumacher, F. R., Campa, D., Albanes, D., Andriole, G., Berndt, S. I., Bueno-de-Mesquita, H. B., Chanock, S. J., Diver, W. R., Ganziano, J. M., Gapstur, S. M., Giovannucci, E., Haiman, C. A., Henderson, B., Hunter, D. J., Johansson, M., Kolonel, L. N., Le Marchand, L., Ma, J., Stampfer, M., Stevens, V. L., Trichopoulos, D., Virtamo, J., Willett, W. C., Yeager, M., Hsing, A. W., Kraft, P. 2012; 21 (1): 212-216

    Abstract

    A recent genome-wide association study (GWAS) of prostate cancer in a Japanese population identified five novel regions not previously discovered in other ethnicities. In this study, we attempt to replicate these five loci in a series of nested prostate cancer case-control studies of European ancestry.We genotyped five single-nucleotide polymorphism (SNP): rs13385191 (chromosome 2p24), rs12653946 (5p15), rs1983891 (6p21), rs339331 (6p22), and rs9600079 (13q22), in 7,956 prostate cancer cases and 8,148 controls from a series of nested case-control studies within the National cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We tested each SNP for association with prostate cancer risk and assessed whether associations differed with respect to disease severity and age of onset.Four SNPs (rs13385191, rs12653946, rs1983891, and rs339331) were significantly associated with prostate cancer risk (P values ranging from 0.01 to 1.1 × 10(-5)). Allele frequencies and ORs were overall lower in our population of European descent than in the discovery Asian population. SNP rs13385191 (C2orf43) was only associated with low-stage disease (P = 0.009, case-only test). No other SNP showed association with disease severity or age of onset. We did not replicate the 13q22 SNP, rs9600079 (P = 0.62).Four SNPs associated with prostate cancer risk in an Asian population are also associated with prostate cancer risk in men of European descent.This study illustrates the importance of evaluation of prostate cancer risk markers across ethnic groups.

    View details for DOI 10.1158/1055-9965.EPI-11-0870-T

    View details for Web of Science ID 000299051500022

    View details for PubMedID 22056501

    View details for PubMedCentralID PMC3253912

  • Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Andriole, G. L., Crawford, E. D., Grubb, R. L., Buys, S. S., Chia, D., Church, T. R., Fouad, M. N., Isaacs, C., Kvale, P. A., Reding, D. J., Weissfeld, J. L., Yokochi, L. A., O'Brien, B., Ragard, L. R., Clapp, J. D., Rathmell, J. M., Riley, T. L., Hsing, A. W., Izmirlian, G., Pinsky, P. F., Kramer, B. S., Miller, A. B., Gohagan, J. K., Prorok, P. C. 2012; 104 (2): 125-132

    Abstract

    The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7-10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial.A total of 76 685 men, aged 55-74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided.Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (P(interaction) = .81), pretrial PSA testing (P(interaction) = .52), and comorbidity (P(interaction) = .68).After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.

    View details for DOI 10.1093/jnci/djr500

    View details for Web of Science ID 000299346200008

    View details for PubMedID 22228146

    View details for PubMedCentralID PMC3260132

  • Genome-wide association study of circulating retinol levels HUMAN MOLECULAR GENETICS Mondul, A. M., Yu, K., Wheeler, W., Zhang, H., Weinstein, S. J., Major, J. M., Cornelis, M. C., Mannisto, S., Hazra, A., Hsing, A. W., Jacobs, K. B., Eliassen, H., Tanaka, T., Reding, D. J., Hendrickson, S., Ferrucci, L., Virtamo, J., Hunter, D. J., Chanock, S. J., Kraft, P., Albanes, D. 2011; 20 (23): 4724-4731

    Abstract

    Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10(-17)) and rs10882272 (P =6.04× 10(-12)). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses' Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10(-5)), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10(-5)). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

    View details for DOI 10.1093/hmg/ddr387

    View details for Web of Science ID 000297049600018

    View details for PubMedID 21878437

    View details for PubMedCentralID PMC3209826

  • Metabolic syndrome and insulin resistance in relation to biliary tract cancer and stone risks: a population-based study in Shanghai, China BRITISH JOURNAL OF CANCER Shebl, F. M., Andreotti, G., Meyer, T. E., Gao, Y., Rashid, A., Yu, K., Shen, M., Wang, B., Han, T., Zhang, B., Stanczyk, F. Z., Hsing, A. W. 2011; 105 (9): 1424-1429

    Abstract

    Serum lipids, diabetes, and obesity, individual components of metabolic syndrome, are associated with biliary tract cancer and stone risk, but the associations of metabolic syndrome or insulin resistance with biliary tract cancers and stones are not well studied.In this population-based case-control study in Shanghai, China (627 biliary tract cancers, 1037 biliary stones, and 959 controls), metabolic syndrome was defined as the presence of any three of the five components, including high waist circumference, high triglycerides, low high-density lipoprotein cholesterol (HDL), high blood pressure, and diabetes. Insulin resistance and β-cell function were assessed, using homeostasis assessment models.Metabolic syndrome was significantly associated with gallbladder cancer (odds ratio (OR)=2.75, 95% confidence interval (95% CI)=1.82-4.15) and biliary stones (OR=1.64, 95% CI=1.24-2.16), with a significant dose effect with increasing number of metabolic syndrome components (P trend <0.0001). The observed association persisted among subjects without a history of diabetes. The association between insulin resistance and gallbladder cancer was borderline (P trend=0.06). There was a significant inverse association between β-cell function and gallbladder cancer risk (P trend <0.001).Our findings suggest that metabolic syndrome and insulin resistance have a role in the aetiology of biliary tract cancers and biliary stones, and if confirmed, they imply that lifestyle control of these factors may lower the risk of biliary stones and biliary tract cancer.

    View details for DOI 10.1038/bjc.2011.363

    View details for Web of Science ID 000296282000026

    View details for PubMedID 21915122

    View details for PubMedCentralID PMC3241543

  • Joint Associations Between Genetic Variants and Reproductive Factors in Glioma Risk Among Women AMERICAN JOURNAL OF EPIDEMIOLOGY Wang, S. S., Hartge, P., Yeager, M., Carreon, T., Ruder, A. M., Linet, M., Inskip, P. D., Black, A., Hsing, A. W., Alavanja, M., Beane-Freeman, L., Safaiean, M., Chanock, S. J., Rajaraman, P. 2011; 174 (8): 901-908

    Abstract

    In a pooled analysis of 4 US epidemiologic studies (1993-2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12-13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.

    View details for DOI 10.1093/aje/kwr184

    View details for Web of Science ID 000295679700004

    View details for PubMedID 21920947

    View details for PubMedCentralID PMC3218628

  • Systematic confirmation study of reported prostate cancer risk-associated single nucleotide polymorphisms in Chinese men CANCER SCIENCE Liu, F., Hsing, A. W., Wang, X., Shao, Q., Qi, J., Ye, Y., Wang, Z., Chen, H., Gao, X., Wang, G., Chu, L. W., Ding, Q., Ouyang, J., Gao, X., Huang, Y., Chen, Y., Gao, Y. T., Zhang, Z., Rao, J., Shi, R., Wu, Q., Wang, M., Zhang, Z., Zhang, Y., Jiang, H., Zheng, J., Hu, Y., Guo, L., Lin, X., Tao, S., Jin, G., Sun, J., Lu, D., Zheng, S. L., Sun, Y., Mo, Z., Xu, J. 2011; 102 (10): 1916-1920

    Abstract

    More than 30 prostate cancer (PCa) risk-associated loci have been identified in populations of European descent by genome-wide association studies. We hypothesized that a subset of these loci might be associated with PCa risk in Chinese men. To test this hypothesis, 33 single nucleotide polymorphisms (SNP), one each from the 33 independent PCa risk-associated loci reported in populations of European descent, were investigated for their associations with PCa risk in a case-control study of Chinese men (1108 cases and 1525 controls). We found that 11 of the 33 SNP were significantly associated with PCa risk in Chinese men (P < 0.05). The reported risk alleles were associated with increased risk for PCa, with allelic odds ratios ranging from 1.12 to 1.44. The most significant locus was located on 8q24 region 2 (rs16901979, P = 5.14 × 10(-9)) with a genome-wide significance (P < (-8) ), and three loci reached the Bonferroni correction significance level (P < 1.52 × 10(-3)), including 8q24 region 1 (rs1447295, P = 7.04 × 10(-6)), 8q24 region 5 (rs10086908, P = 9.24 × 10(-4)) and 8p21 (rs1512268, P = 9.39 × 10(-4)). Our results suggest that a subset of the PCa risk-associated SNP discovered by genome-wide association studies among men of European descent is also associated with PCa risk in Chinese men. This finding provides evidence of ethnic differences and similarity in genetic susceptibility to PCa. Genome-wide association studies in Chinese men are needed to identify Chinese-specific PCa risk-associated SNP.

    View details for DOI 10.1111/j.1349-7006.2011.02036.x

    View details for Web of Science ID 000295328800011

    View details for PubMedID 21756274

    View details for PubMedCentralID PMC3581323

  • Repeat polymorphisms in estrogen metabolism genes and prostate cancer risk: results from the Prostate Cancer Prevention Trial CARCINOGENESIS Tang, L., Yao, S., Till, C., Goodman, P. J., Tangen, C. M., Wu, Y., Kristal, A. R., Platz, E. A., Neuhouser, M. L., Stanczyk, F. Z., Reichardt, J. K., Santella, R. M., Hsing, A., Hoque, A., Lippman, S. M., Thompson, I. M., Ambrosone, C. B. 2011; 32 (10): 1500-1506

    Abstract

    The etiology of prostate cancer remains elusive, although steroid hormones probably play a role. Considering the carcinogenic potential of estrogen metabolites as well as altered intraprostatic estrogen biosynthesis during the development of prostate cancer, we investigated associations between repeat polymorphisms of three key estrogen-related genes (CYP11A1, CYP19A1, UGT1A1) and risk of prostate cancer in the Prostate Cancer Prevention Trial (PCPT), designed to test finasteride versus placebo as a chemoprevention agent. Using data and specimens from 1154 cases and 1351 controls who were frequency matched on age, family history of prostate cancer and PCPT treatment arm, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) separately in the placebo and finasteride arms. Among men in the placebo arm, CYP19A1 7/8 genotype carriers had a significantly higher risk of prostate cancer compared with those with the 7/7 genotype (OR = 1.70, 95% CI = 1.16-2.5), regardless of Gleason grade. This genotype was also associated with elevated serum estrogen levels. For the (TA)(n) repeat polymorphism in UGT1A1, the heterozygous short (<7 repeats)/long (≥7 repeats) genotype was significantly associated with the risk of low-grade prostate cancer (OR = 1.34, 95% CI = 1.05-1.70) compared with the short/short genotype. No significant association was found with CYP11A1. These associations were not observed among men in the finasteride arm. The results indicate that repeat polymorphisms in genes involved in estrogen biosynthesis and metabolism may influence risk of prostate cancer but that their effects may be modified by factors altering hormone metabolism, such as finasteride treatment.

    View details for DOI 10.1093/carcin/bgr139

    View details for Web of Science ID 000295173200013

    View details for PubMedID 21771722

    View details for PubMedCentralID PMC3179424

  • Medical history and the risk of biliary tract cancers in Shanghai, China: implications for a role of inflammation CANCER CAUSES & CONTROL Andreotti, G., Liu, E., Gao, Y., Safaeian, M., Rashid, A., Shen, M., Wang, B., Deng, J., Han, T., Zhang, B., Hsing, A. W. 2011; 22 (9): 1289-1296

    Abstract

    Several lines of evidence suggest that inflammation may play a role in the etiology of biliary tract cancers. To examine further the role of inflammation, we evaluated the associations between self-reported inflammatory-related medical conditions and the risk of biliary tract cancers in a population-based case-control study in Shanghai, China. Our analysis included 368 gallbladder cancer cases, 191 bile duct cancer cases, 68 ampulla of Vater cancer cases, and 959 healthy subjects. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for biliary tract cancers in relation to six inflammation-related conditions. Gallbladder cancer was significantly associated with cholecystitis occurring at least 5 years prior to interview (OR = 1.7, 95% CI 1.1-2.9). Even though biliary stones did not significantly modify the associations between cholecystitis and gallbladder cancer, 90% of the gallbladder cancer cases with cholecystitis also had biliary stones, indicating that stones likely play an important role in the link between cholecystitis and gallbladder cancer. Among subjects who smoked and drank alcohol, a history of gastric (OR = 4.3, 95% CI 1.2-15.0) or duodenal ulcers (OR = 3.7, 1.2-12.0) was associated with an excess risk of gallbladder cancer. Although the mechanisms are unclear, our results further support the role for inflammation in the etiology of biliary tract cancers.

    View details for DOI 10.1007/s10552-011-9802-z

    View details for Web of Science ID 000293296200007

    View details for PubMedID 21744094

  • Serum estrogen levels and prostate cancer risk in the prostate cancer prevention trial: a nested case-control study CANCER CAUSES & CONTROL Yao, S., Till, C., Kristal, A. R., Goodman, P. J., Hsing, A. W., Tangen, C. M., Platz, E. A., Stanczyk, F. Z., Reichardt, J. K., Tang, L., Neuhouser, M. L., Santella, R. M., Figg, W. D., Price, D. K., Parnes, H. L., Lippman, S. M., Thompson, I. M., Ambrosone, C. B., Hoque, A. 2011; 22 (8): 1121-1131

    Abstract

    Finasteride reduces prostate cancer risk by blocking the conversion of testosterone to dihydrotestosterone. However, whether finasteride affects estrogens levels or change in estrogens affects prostate cancer risk is unknown.These questions were investigated in a case-control study nested within the prostate cancer prevention trial (PCPT) with 1,798 biopsy-proven prostate cancer cases and 1,798 matched controls.Among men on placebo, no relationship of serum estrogens with risk of prostate cancer was found. Among those on finasteride, those in the highest quartile of baseline estrogen levels had a moderately increased risk of Gleason score < 7 prostate cancer (for estrone, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.06-2.15; for estradiol, OR = 1.50, 95% CI = 1.03-2.18). Finasteride treatment increased serum estrogen concentrations; however, these changes were not associated with prostate cancer risk.Our findings confirm those from previous studies that there are no associations of serum estrogen with prostate cancer risk in untreated men. In addition, finasteride results in a modest increase in serum estrogen levels, which are not related to prostate cancer risk. Whether finasteride is less effective in men with high serum estrogens, or finasteride interacts with estrogen to increase cancer risk, is uncertain and warrants further investigation.

    View details for DOI 10.1007/s10552-011-9787-7

    View details for Web of Science ID 000292928300005

    View details for PubMedID 21667068

    View details for PubMedCentralID PMC3139891

  • A Reproducible and High-Throughput HPLC/MS Method To Separate Sarcosine from alpha- and beta-Alanine and To Quantify Sarcosine in Human Serum and Urine ANALYTICAL CHEMISTRY Meyer, T. E., Fox, S. D., Issaq, H. J., Xu, X., Chu, L. W., Veenstra, T. D., Hsing, A. W. 2011; 83 (14): 5735-5740

    Abstract

    While sarcosine was recently identified as a potential urine biomarker for prostate cancer, further studies have cast doubt on its utility to diagnose this condition. The inconsistent results may be due to the fact that alanine and sarcosine coelute on an HPLC reversed-phase column and the mass spectrometer cannot differentiate between the two isomers, since the same parent/product ions are generally used to measure them. In this study, we developed a high-throughput liquid chromatography-mass spectrometry (LC-MS) method that resolves sarcosine from alanine isomers, allowing its accurate quantification in human serum and urine. Assay reproducibility was determined using the coefficient of variation (CV) and intraclass correlation coefficient (ICC) in serum aliquots from 10 subjects and urine aliquots from 20 subjects across multiple analytic runs. Paired serum/urine samples from 42 subjects were used to evaluate sarcosine serum/urine correlation. Both urine and serum assays gave high sensitivity (limit of quantitation of 5 ng/mL) and reproducibility (serum assay, intra- and interassay CVs < 3% and ICCs > 99%; urine assay, intra-assay CV = 7.7% and ICC = 98.2% and interassay CV = 12.3% and ICC = 94.2%). In conclusion, this high-throughput LC-MS method is able to resolve sarcosine from α- and β-alanine and is useful for quantifying sarcosine in serum and urine samples.

    View details for DOI 10.1021/ac201003r

    View details for Web of Science ID 000292892000036

    View details for PubMedID 21635006

  • Dietary carbohydrate, glycemic index, glycemic load, and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort CANCER CAUSES & CONTROL Shikany, J. M., Flood, A. P., Kitahara, C. M., Hsing, A. W., Meyer, T. E., Willcox, B. J., Redden, D. T., Ziegler, R. G. 2011; 22 (7): 995-1002

    Abstract

    To evaluate the associations between dietary carbohydrate, glycemic index (GI), glycemic load (GL), and incident prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.Between September 1993 and September 2000, 38,343 men were randomized to the screening arm of the trial at one of 10 PLCO centers. A food frequency questionnaire administered at baseline assessed usual dietary intake over the preceding 12 months. Prostate cancer was ascertained by medical follow-up of suspicious screening results and annual mailed questionnaires and confirmed with medical records. Cox proportional hazards regression was used to model the associations of carbohydrate, GI, and GL with prostate cancer risk.During follow-up (median = 9.2 years), 2,436 incident prostate cancers were identified among 30,482 eligible participants. Overall, there were no associations of baseline carbohydrate, GI, or GL with incident prostate cancer in minimally or fully adjusted models. There were no associations when the 228 advanced and 2,208 non-advanced cancers were analyzed separately.Dietary carbohydrate, GI, and GL were not associated with incident prostate cancer in PLCO. The narrow range of GI in this cohort may have limited our ability to detect associations, an issue that future studies should address.

    View details for DOI 10.1007/s10552-011-9772-1

    View details for Web of Science ID 000291742700006

    View details for PubMedID 21553078

    View details for PubMedCentralID PMC4470253

  • High prevalence of polyclonal hypergamma-globulinemia in adult males in Ghana, Africa AMERICAN JOURNAL OF HEMATOLOGY Buadi, F., Hsing, A. W., Katzmann, J. A., Pfeiffer, R. M., Waxman, A., Yeboah, E. D., Biritwum, R. B., Tettey, Y., Adjei, A., Chu, L. W., Demarzo, A., Netto, G. J., Dispenzieri, A., Kyle, R. A., Rajkumar, S. V., Landgren, O. 2011; 86 (7): 554-558

    Abstract

    Chronic antigenic stimulation is associated with hypergamma-globulinemia. Higher rates of hypergamma-globulinemia in tropical populations are maintained even with migration to temperate regions. We conducted a population-based screening study to assess the prevalence and risk factors for hypergamma-globulinemia in Ghana, Africa. 917 Ghanaian males (50-74 years) underwent in-person interviews and health examinations. Serum from all persons was analyzed by electrophoresis performed on agarose gel; serum with a discrete/localized band was subjected to immunofixation. 54 persons with monoclonal proteins were excluded and 17 samples were insufficient for analysis. Using logistic regression and Chi-square statistics we analyzed patterns of hypergamma-globulinemia. Among 846 study subjects, the median γ-globulin level was 1.86 g/dL. On the basis of a U.S. reference, 616 (73%) had hypergamma-globulinemia (>1.6 g/dL) and 178 (21%) had γ-globulin levels >2.17 gm/dl. On multivariate analyses, lower education status (P = 0.0013) and never smoking (P = 0.038) were associated with increased γ-globulin levels. Self-reported history of syphilis was associated with hypergamma-globulinemia. We conclude that three quarters of this population-based adult Ghanaian male sample had hypergamma-globulinemia with γ-globulin levels >1.6 g/dL. Future studies are needed to uncover genetic and environmental underpinnings of our finding, and to define the relationship between hypergamma-globulinemia, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.

    View details for DOI 10.1002/ajh.22040

    View details for Web of Science ID 000291938000006

    View details for PubMedID 21674575

    View details for PubMedCentralID PMC3736856

  • Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21 NATURE GENETICS Haiman, C. A., Chen, G. K., Blot, W. J., Strom, S. S., Berndt, S. I., Kittles, R. A., Rybicki, B. A., Isaacs, W. B., Ingles, S. A., Stanford, J. L., Diver, W. R., Witte, J. S., Hsing, A. W., Nemesure, B., Rebbeck, T. R., Cooney, K. A., Xu, J., Kibel, A. S., Hu, J. J., John, E. M., Gueye, S. M., Watya, S., Signorello, L. B., Hayes, R. B., Wang, Z., Yeboah, E., Tettey, Y., Cai, Q., Kolb, S., Ostrander, E. A., Zeigler-Johnson, C., Yamamura, Y., Neslund-Dudas, C., Haslag-Minoff, J., Wu, W., Thomas, V., Allen, G. O., Murphy, A., Chang, B., Zheng, S. L., Leske, M. C., Wu, S., Ray, A. M., Hennis, A. J., Thun, M. J., Carpten, J., Casey, G., Carter, E. N., Duarte, E. R., Xia, L. Y., Sheng, X., Wan, P., Pooler, L. C., Cheng, I., Monroe, K. R., Schumacher, F., Le Marchand, L., Kolonel, L. N., Chanock, S. J., Van Den Berg, D., Stram, D. O., Henderson, B. E. 2011; 43 (6): 570-U103

    Abstract

    In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

    View details for DOI 10.1038/ng.839

    View details for Web of Science ID 000291017000015

    View details for PubMedID 21602798

    View details for PubMedCentralID PMC3102788

  • Evolution and Taxonomic Classification of Human Papillomavirus 16 (HPV16)-Related Variant Genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67 PLOS ONE Chen, Z., Schiffman, M., Herrero, R., DeSalle, R., Anastos, K., Segondy, M., Sahasrabuddhe, V. V., Gravitt, P. E., Hsing, A. W., Burk, R. D. 2011; 6 (5)

    Abstract

    Human papillomavirus 16 (HPV16) species group (alpha-9) of the Alphapapillomavirus genus contains HPV16, HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. These HPVs account for 75% of invasive cervical cancers worldwide. Viral variants of these HPVs differ in evolutionary history and pathogenicity. Moreover, a comprehensive nomenclature system for HPV variants is lacking, limiting comparisons between studies.DNA from cervical samples previously characterized for HPV type were obtained from multiple geographic regions to screen for novel variants. The complete 8 kb genomes of 120 variants representing the major and minor lineages of the HPV16-related alpha-9 HPV types were sequenced to capture maximum viral heterogeneity. Viral evolution was characterized by constructing phylogenic trees based on complete genomes using multiple algorithms. Maximal and viral region specific divergence was calculated by global and pairwise alignments. Variant lineages were classified and named using an alphanumeric system; the prototype genome was assigned to the A lineage for all types.The range of genome-genome sequence heterogeneity varied from 0.6% for HPV35 to 2.2% for HPV52 and included 1.4% for HPV31, 1.1% for HPV33, 1.7% for HPV58 and 1.1% for HPV67. Nucleotide differences of approximately 1.0% - 10.0% and 0.5%-1.0% of the complete genomes were used to define variant lineages and sublineages, respectively. Each gene/region differs in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) /noncoding region 2 (NCR2) >upstream regulatory region (URR)> E6/E7 > E2/L2 > E1/L1.These data define maximum viral genomic heterogeneity of HPV16-related alpha-9 HPV variants. The proposed nomenclature system facilitates the comparison of variants across epidemiological studies. Sequence diversity and phylogenies of this clinically important group of HPVs provides the basis for further studies of discrete viral evolution, epidemiology, pathogenesis and preventative/therapeutic interventions.

    View details for DOI 10.1371/journal.pone.0020183

    View details for Web of Science ID 000291052500039

    View details for PubMedID 21673791

    View details for PubMedCentralID PMC3103539

  • Obesity and Thyroid Cancer Risk among US Men and Women: A Pooled Analysis of Five Prospective Studies CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kitahara, C. M., Platz, E. A., Freeman, L. E., Hsing, A. W., Linet, M. S., Park, Y., Schairer, C., Schatzkin, A., Shikany, J. M., de Gonzalez, A. B. 2011; 20 (3): 464-472

    Abstract

    Thyroid cancer incidence has risen dramatically in the United States since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain.We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex.Over follow-up (mean=10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI [per 5 kg/m2: HR in women, 1.16 (95% CI, 1.08-1.24); HR in men, 1.21 (95% CI, 0.97-1.49)]. There was no significant heterogeneity between studies (both P>0.05). For women and men combined, the HRs for overweight (25.0-29.9 kg/m2) and obesity (≥30 kg/m2) compared with normal-weight (18.5-24.9 kg/m2) were 1.20 (95% CI, 1.04-1.38) and 1.53 (95% CI, 1.31-1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18-20) with thyroid cancer risk was also observed [per 5-kg/m2 increase: HR, 1.18 (95% CI, 1.03-1.35)].BMI was positively associated with thyroid cancer risk in both men and women.Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer.

    View details for DOI 10.1158/1055-9965.EPI-10-1220

    View details for Web of Science ID 000288067200007

    View details for PubMedID 21266520

    View details for PubMedCentralID PMC3079276

  • Cholesterol metabolism gene polymorphisms and the risk of biliary tract cancers and stones: a population-based case-control study in Shanghai, China CARCINOGENESIS Xu, H., Cheng, J., Andreotti, G., Gao, Y., Rashid, A., Wang, B., Shen, M., Chu, L. W., Yu, K., Hsing, A. W. 2011; 32 (1): 58-62

    Abstract

    Biliary tract cancers are rare but fatal malignancies, with increasing incidence in Shanghai, China. Gallstones, the primary risk factor for biliary tract cancer, typically result from oversaturation of cholesterol in bile. We examined the association of five variants in three lipid metabolism-related genes (CETP, ABCG8 and LRPAP1) and biliary tract cancers and stones in a population-based case-control study in Shanghai, China. We included 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct and 53 ampulla of Vater cancer cases), 429 biliary stone cases and 447 population controls. Carriers of the CG genotype of ABCG8 rs11887534 had higher risk of biliary stones [odds ratio (OR) = 2.3, 95% confidence interval (CI) 0.82-6.5), gallbladder cancer (OR = 4.3, 95% CI 1.7-10.4) and bile duct cancer (OR = 1.94, 95% CI 0.64-5.91), compared with carriers of the GG genotype. Analysis stratified by gender showed both male and female carriers of CG rs11887534 had higher risks of biliary stones and gallbladder cancer, although the association was statistically significant only for women and gallbladder cancer (OR = 6.3, 95% CI 1.86-22.3). Carriers of the ABCG8 haplotype C-C (rs4148217-rs11887534) had a 4.16-fold (95% CI 1.71-10.1) risk of gallbladder cancer compared with those carrying the C-G haplotype. Our findings suggest that ABCG8 rs11887534, identified as a gallstone risk single-nucleotide polymorphism by whole genome scan, is also associated with an increased risk of biliary tract cancer.

    View details for DOI 10.1093/carcin/bgq194

    View details for Web of Science ID 000286303000009

    View details for PubMedID 21062971

  • Chronic typhoid infection and the risk of biliary tract cancer and stones in Shanghai, China INFECTIOUS AGENTS AND CANCER Safaeian, M., Gao, Y., Sakoda, L. C., Quraishi, S. M., Rashid, A., Wang, B., Chen, J., Pruckler, J., Mintz, E., Hsing, A. W. 2011; 6
  • Validation of Genome-Wide Prostate Cancer Associations in Men of African Descent CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chang, B., Spangler, E., Gallagher, S., Haiman, C. A., Henderson, B., Isaacs, W., Benford, M. L., Kidd, L. R., Cooney, K., Strom, S., Ingles, S. A., Stern, M. C., Corral, R., Joshi, A. D., Xu, J., Giri, V. N., Rybicki, B., Neslund-Dudas, C., Kibel, A. S., Thompson, I. M., Leach, R. J., Ostrander, E. A., Stanford, J. L., Witte, J., Casey, G., Eeles, R., Hsing, A. W., Chanock, S., Hu, J. J., John, E. M., Park, J., Stefflova, K., Zeigler-Johnson, C., Rebbeck, T. R. 2011; 20 (1): 23-32

    Abstract

    Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent.We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci.We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2.We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations.The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent.

    View details for DOI 10.1158/1055-9965.EPI-10-0698

    View details for Web of Science ID 000285972800003

    View details for PubMedID 21071540

    View details for PubMedCentralID PMC3110616

  • Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3 NATURE GENETICS Purdue, M. P., Johansson, M., Zelenika, D., Toro, J. R., Scelo, G., Moore, L. E., Prokhortchouk, E., Wu, X., Kiemeney, L. A., Gaborieau, V., Jacobs, K. B., Chow, W., Zaridze, D., Matveev, V., Lubinski, J., Trubicka, J., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Bucur, A., Bencko, V., Foretova, L., Janout, V., Boffetta, P., Colt, J. S., Davis, F. G., Schwartz, K. L., Banks, R. E., Selby, P. J., Harnden, P., Berg, C. D., Hsing, A. W., Grubb, R. L., Boeing, H., Vineis, P., Clavel-Chapelon, F., Palli, D., Tumino, R., Krogh, V., Panico, S., Duell, E. J., Quiros, J. R., Sanchez, M., Navarro, C., Ardanaz, E., Dorronsoro, M., Khaw, K., Allen, N. E., Bueno-de-Mesquita, H. B., Peeters, P. H., Trichopoulos, D., Linseisen, J., Ljungberg, B., Overvad, K., Tjonneland, A., Romieu, I., Riboli, E., Mukeria, A., Shangina, O., Stevens, V. L., Thun, M. J., Diver, W. R., Gapstur, S. M., Pharoah, P. D., Easton, D. F., Albanes, D., Weinstein, S. J., Virtamo, J., Vatten, L., Hveem, K., Njolstad, I., Tell, G. S., Stoltenberg, C., Kumar, R., Koppova, K., Cussenot, O., Benhamou, S., Oosterwijk, E., Vermeulen, S. H., Aben, K. K., van der Marel, S. L., Ye, Y., Wood, C. G., Pu, X., Mazur, A. M., Boulygina, E. S., Chekanov, N. N., Foglio, M., Lechner, D., Gut, I., Heath, S., Blanche, H., Hutchinson, A., Thomas, G., Wang, Z., Yeager, M., Fraumeni, J. F., Skryabin, K. G., McKay, J. D., Rothman, N., Chanock, S. J., Lathrop, M., Brennan, P. 2011; 43 (1): 60-U83

    Abstract

    We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10⁻⁸) and rs7579899 (P = 2.3 × 10⁻⁹), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10⁻¹⁴). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10⁻⁸). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.

    View details for DOI 10.1038/ng.723

    View details for Web of Science ID 000285683500017

    View details for PubMedID 21131975

    View details for PubMedCentralID PMC3049257

  • Androgen Receptor CAG Repeat Length and Association With Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial JOURNAL OF UROLOGY Price, D. K., Chau, C. H., Till, C., Goodman, P. J., Baum, C. E., Ockers, S. B., English, B. C., Minasian, L., Parnes, H. L., Hsing, A. W., Reichardt, J. K., Hoque, A., Tangen, C. M., Kristal, A. R., Thompson, I. M., Figg, W. D. 2010; 184 (6): 2297-2302

    Abstract

    We investigated the association between the length of the polymorphic trinucleotide CAG microsatellite repeats in exon 1 of the AR gene and the risk of prostate cancer.This is a nested case-control study of 1,159 cases and 1,353 controls from the Prostate Cancer Prevention Trial, a randomized, placebo controlled trial testing whether the 5α-reductase inhibitor finasteride could decrease the 7-year prevalence of prostate cancer. During the course of the trial men underwent annual digital rectal examination and prostate specific antigen measurement. Prostate biopsy was recommended in all men with abnormal digital rectal examination or finasteride adjusted prostate specific antigen greater than 4.0 ng/ml. Cases were drawn from men with biopsy determined prostate cancer identified by for cause or end of study biopsy. Controls were selected from men who completed the end of study biopsy.Mean CAG repeat length did not differ between cases and controls. The frequency distribution of cases and controls for the AR CAG repeat length was similar. There were no significant associations of CAG repeat length with prostate cancer risk when stratified by treatment arm (finasteride or placebo), or when combined. There was also no significant association between CAG repeat length and the risk of low or high grade prostate cancer.There is no association of AR CAG repeat length with prostate cancer risk. Knowledge of AR CAG repeat length provides no clinically useful information to predict prostate cancer risk.

    View details for DOI 10.1016/j.juro.2010.08.005

    View details for Web of Science ID 000284037900027

    View details for PubMedID 20952028

    View details for PubMedCentralID PMC3930175

  • Transition of a Clinical Trial into Translational Research: The Prostate Cancer Prevention Trial Experience CANCER PREVENTION RESEARCH Goodman, P. J., Tangen, C. M., Kristal, A. R., Thompson, I. M., Lucia, M. S., Platz, E. A., Figg, W. D., Hoque, A., Hsing, A., Neuhouser, M. L., Parnes, H. L., Reichardt, J. K., Santella, R. M., Till, C., Lippman, S. M. 2010; 3 (12): 1523-1533

    Abstract

    Large clinical trials provide a tremendous opportunity to integrate correlative, comprehensive biological studies with invaluable repositories of biospecimens and clinical and other data from the trial. The Prostate Cancer Prevention Trial (PCPT) was a phase III randomized, double-blind, placebo-controlled clinical trial of finasteride in 18,882 men. Clinical data and blood and tissue specimens were collected at baseline and throughout the study, offering an opportunity to create a program project to investigate hypotheses related to the biology underlying the PCPT findings as well as the etiology and risk of prostate cancer. The transition of the randomized PCPT into this translational and epidemiologic scientific investigation required extensive planning and coordination. Five individual but interrelated projects were brought together with the underlying program theme of the genetic, metabolic, and environmental factors associated with the risks of overall and high-grade prostate cancer and how these factors affected the efficacy of finasteride in preventing cancer. All projects with serum-based measures use a single, shared, nested case-control sample of participants so that each subject provides a more complete biomarker and genetic profile for the evaluation of joint effects of these factors. Strengths of this program include the following: 1) the control group contains only men who are negative for biopsy-detected cancer, 2) the statistical methods to evaluate associations of risk factors with disease are shared across all projects, 3) the large number of cancer cases with fully characterized genetic, metabolic, and behavioral exposures, 4) a central pathology core histopathologically classified the prostate cancer, and 5) cancer cases identified during the PCPT reflect the characteristics of cases currently being detected in the prostate-specific antigen screening era, leading to contemporary and highly relevant results. This article describes the comprehensive methodology and multidisciplinary collaborations, both national and international, essential to a major risk-modeling research program. We provide a framework for doing collaborative research in an international setting structured around a common theme of a clinical trial.

    View details for DOI 10.1158/1940-6207.CAPR-09-0256

    View details for Web of Science ID 000285189400005

    View details for PubMedID 21149329

    View details for PubMedCentralID PMC3058741

  • Finasteride metabolism and pharmacogenetics: new approaches to personalized prevention of prostate cancer FUTURE ONCOLOGY Hulin-Curtis, S. L., Petit, D., Figg, W. D., Hsing, A. W., Reichardt, J. K. 2010; 6 (12): 1897-1913

    Abstract

    Incidences of prostate cancer in most countries are increasing owing to better detection methods; however, prevention with the use of finasteride, a very effective steroid 5α-reductase type II inhibitor, has been met with mixed success. A wide interindividual variation in response exists and is thought to be due to heritable factors. This article summarizes the literature that attempts to elucidate the molecular mechanisms of finasteride in terms of its metabolism, excretion and interaction with endogenous steroid molecules. We describe previously reported genetic variations of steroid-metabolizing genes and their potential association with finasteride efficacy. Based on the literature, we outline directions of research that may contribute to understanding the interindividual variation in finasteride prevention and to the future development of personalized medicine.

    View details for DOI 10.2217/FON.10.149

    View details for Web of Science ID 000297100400014

    View details for PubMedID 21142863

  • Association between Genetic Variants in the 8q24 Cancer Risk Regions and Circulating Levels of Androgens and Sex Hormone-Binding Globulin CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chu, L. W., Meyer, T. E., Li, Q., Menashe, I., Yu, K., Rosenberg, P. S., Huang, W., Quraishi, S. M., Kaaks, R., Weiss, J. M., Hayes, R. B., Chanock, S. J., Hsing, A. W. 2010; 19 (7): 1848-1854

    Abstract

    Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder.To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphisms (SNPs) in the 8q24 risk regions spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, 3alphadiol G, and bioavailable testosterone), and sex hormone-binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log-transformed biomarker levels.Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P < 1.1 x 10(-3)) and bioavailable testosterone (P < 6.3 x 10(-4)). Suggestive associations were seen for a cluster of nine SNPs in prostate cancer risk region 1 and androstenedione (P < 0.05).These preliminary findings require confirmation in larger studies but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions might correlate with androgen levels.These results might provide some clues for the strong link between 8q24 and prostate cancer risk.

    View details for DOI 10.1158/1055-9965.EPI-10-0101

    View details for Web of Science ID 000279590100021

    View details for PubMedID 20551303

    View details for PubMedCentralID PMC2901401

  • Diabetes in relation to biliary tract cancer and stones: a population-based study in Shanghai, China BRITISH JOURNAL OF CANCER Shebl, F. M., Andreotti, G., Rashid, A., Gao, Y., Yu, K., Shen, M., Wang, B., Li, Q., Han, T., Zhang, B., Fraumeni, J. F., Hsing, A. W. 2010; 103 (1): 115-119

    Abstract

    Biliary tract cancers are rare but fatal malignancies. Diabetes has been related to biliary stones, but its association with biliary tract cancers is less conclusive.In a population-based case-control study of 627 cancers, 1037 stones, and 959 controls in Shanghai, China, we examined the association between diabetes and the risks of biliary tract cancer and stones, as well as the effect of potential mediating factors, including serum lipids and biliary stones (for cancer), contributing to the causal pathway from diabetes to biliary diseases.Independent of body mass index (BMI), diabetes was significantly associated with gallbladder cancer and biliary stones ((odds ratio (OR) (95% confidence interval)=2.6 (1.5-4.7) and 2.0 (1.2-3.3), respectively). Biliary stones and low serum levels of high-density lipoprotein (HDL) were significant mediators of the diabetes effect on gallbladder cancer risk, accounting for 60 and 17% of the diabetes effect, respectively. High-density lipoprotein was also a significant mediator of the diabetes effect on biliary stones, accounting for 18% of the diabetes effect.Independent of BMI, diabetes is a risk factor for gallbladder cancer, but its effect is mediated in part by biliary stones and serum HDL levels, suggesting that gallbladder cancer risk may be reduced by controlling diabetes, stones, and HDL levels.

    View details for DOI 10.1038/sj.bjc.6605706

    View details for Web of Science ID 000279374800016

    View details for PubMedID 20517308

    View details for PubMedCentralID PMC2905288

  • Intra-individual variation in serum C-reactive protein over 4 years: an implication for epidemiologic studies CANCER CAUSES & CONTROL Platz, E. A., Sutcliffe, S., De Marzo, A. M., Drake, C. G., Rifai, N., Hsing, A. W., Hoque, A., Neuhouser, M. L., Goodman, P. J., Kristal, A. R. 2010; 21 (6): 847-851

    Abstract

    Data on long-term intra-individual variability in high-sensitivity C-reactive protein (hsCRP) are needed to determine whether one measurement adequately reflects usual levels in prospective studies of on the etiology of cancer and other chronic diseases; when not reflective, the ability to statistically detect modest to moderate associations is reduced. The authors estimated the size of this source of variability and consequent attenuation of the relative risk (RR).High-sensitivity C-reactive protein (hsCRP) concentration was measured using a high-sensitivity immunoturbidometric assay in sera collected at years 2, 4, and 6 from 50 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT). After natural logarithm-transformation of hsCRP, analysis of variance was used to estimate the within- and between-individual variances from which the intra-class correlation coefficient (ICC) was calculated.The observed RR due to an ICC < 1 was calculated by e((ln true RR*ICC)) for a range of true RRs. The 4-year ICC was 0.66. Measuring hsCRP once and assuming no other error, if the true RRs were 1.50, 2.00, and 3.00 when comparing high with low concentration, then the observed RRs would be 1.31, 1.58, and 2.06, respectively.Investigators planning to measure hsCRP only once should design adequately sized studies to preserve inferences for hypothesized modest to moderate RRs.

    View details for DOI 10.1007/s10552-010-9511-z

    View details for Web of Science ID 000277709800006

    View details for PubMedID 20135215

    View details for PubMedCentralID PMC3010861

  • Polymorphisms of estrogen receptors and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China CARCINOGENESIS Park, S. K., Andreotti, G., Rashid, A., Chen, J., Rosenberg, P. S., Yu, K., Olsen, J., Gao, Y., Deng, J., Sakoda, L. C., Zhang, M., Shen, M., Wang, B., Han, T., Zhang, B., Yeager, M., Chanock, S. J., Hsing, A. W. 2010; 31 (5): 842-846

    Abstract

    Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case-control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1-2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9-4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4-5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3' of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3-8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men.

    View details for DOI 10.1093/carcin/bgq038

    View details for Web of Science ID 000277447600011

    View details for PubMedID 20172949

    View details for PubMedCentralID PMC2864412

  • Limitations of Direct Immunoassays for Measuring Circulating Estradiol Levels in Postmenopausal Women and Men in Epidemiologic Studies CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Stanczyk, F. Z., Jurow, J., Hsing, A. W. 2010; 19 (4): 903-906

    Abstract

    Serum estradiol (E(2)) serves as an important diagnostic marker in a variety of clinical conditions. In epidemiologic studies, E(2) is commonly used to define the etiologic role of estrogen in hormone-related cancers and chronic conditions. Having an accurate and reliable E(2) assay is of critical importance in these studies, especially when measuring the very low E(2) levels (<30 pg/mL) common in postmenopausal women and men, and for discerning the relatively small (usually <20%) case-control differences in E(2) levels. Because E(2) is metabolized to >100 metabolites in the body, some of which cross-react with E(2) antibodies, direct RIAs without purification steps lack specificity for E(2) and can substantially overestimate E(2) levels. Although direct E(2) RIAs using commercial kits are simpler, less time consuming, and less expensive and require less sample volume than conventional RIAs with preceding purification steps, their lack of sensitivity and specificity makes them invalid for measuring circulating E(2) levels in epidemiologic studies of postmenopausal women or men. Instead, we recommend the use of a well-validated RIA with purification steps to improve sensitivity and specificity and to help achieve the necessary accuracy and reliability needed for epidemiologic studies.

    View details for DOI 10.1158/1055-9965.EPI-10-0081

    View details for Web of Science ID 000278484400002

    View details for PubMedID 20332268

  • Simultaneous Recovery of DNA and RNA from Formalin-Fixed Paraffin-Embedded Tissue and Application in Epidemiologic Studies (Retracted article. See vol. 23, pg. 1132, 2014) CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Huang, W., Sheehy, T. M., Moore, L. E., Hsing, A. W., Purdue, M. P. 2010; 19 (4): 973-977

    Abstract

    Analysis of DNA, RNA, and protein extracted from tissue specimens in epidemiologic studies is useful for assessing etiologic heterogeneity, mechanisms of carcinogenesis, and biomarkers for prognosis and prediction of treatment responses. Fresh-frozen tissue samples may provide optimal quality nucleic acids, but pose multiple logistical considerations, including rapid access to tissues before histopathologic examination and specialized equipment for freezing, transport, and storage; in addition, morphology is often compromised. In contrast, formalin-fixed paraffin-embedded (FFPE) tissue samples, including enormous archives of existing specimens, represent a valuable source of retrospective biological material for epidemiologic research, although presenting different limitations compared with frozen samples. Recent efforts have made progress toward enhancing the utility of FFPE specimens for molecular analyses, including DNA studies, and increasingly for RNA and other macromolecules. Here, we report the method that we used to simultaneously recover DNA and RNA from FFPE tissue specimens with appreciable quantity and quality and discuss briefly the application of tumor markers in epidemiologic studies.

    View details for DOI 10.1158/1055-9965.EPI-10-0091

    View details for Web of Science ID 000278484400014

    View details for PubMedID 20332269

    View details for PubMedCentralID PMC2864144

  • Serum Oxidized Protein and Prostate Cancer Risk within the Prostate Cancer Prevention Trial CANCER PREVENTION RESEARCH Hoque, A., Ambrosone, C. B., Till, C., Goodman, P. J., Tangen, C., Kristal, A., Lucia, S., Wang, Q., Kappil, M., Thompson, I., Hsing, A. W., Parnes, H., Santella, R. M. 2010; 3 (4): 478-483

    Abstract

    To evaluate the role of oxidative stress in prostate cancer risk, we analyzed serum levels of protein carbonyl groups in 1,808 prostate cancer cases and 1,805 controls, nested in the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial that found finasteride decreased prostate cancer risk. There were no significant differences in protein carbonyl levels in baseline samples between those later diagnosed with prostate cancer and those without at the end of study biopsy. Adjusted odds ratios and 95% confidence intervals (95% CI) for the 4th quartile of protein carbonyl level for the combined, placebo, and finasteride arms were 1.03 (95% CI, 0.85-1.24), 0.88 (95% CI, 0.69-1.12), and 1.27 (95% CI, 0.94-1.71), respectively. There were no significant associations between carbonyl level and risk when analyzing high-grade and low-grade disease separately, nor did finasteride affect protein oxidation levels. The results of this large nested case-control study do not support the hypothesis that oxidative stress, at least as measured by protein carbonyl level, plays a role in prostate cancer.

    View details for DOI 10.1158/1940-6207.CAPR-09-0201

    View details for Web of Science ID 000276263600013

    View details for PubMedID 20332306

    View details for PubMedCentralID PMC2853720

  • Measuring Serum Melatonin in Epidemiologic Studies CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hsing, A. W., Meyer, T. E., Niwa, S., Quraishi, S. M., Chu, L. W. 2010; 19 (4): 932-937

    Abstract

    Epidemiologic data on serum melatonin, a marker of circadian rhythms, and cancer are sparse due largely to the lack of reliable assays with high sensitivity to detect relatively low melatonin levels in serum collected during daylight, as commonly available in most epidemiologic studies.To help expand epidemiologic research on melatonin, we assessed the reproducibility and refined a currently available melatonin RIA, and evaluated its application to epidemiologic investigations by characterizing melatonin levels in serum, urine, and/or plasma in 135 men from several ethnic groups.Reproducibility was high for the standard 1.0-mL serum [mean coefficient of variation (CV), 6.9%; intraclass correlation coefficient (ICC), 97.4%; n = 2 serum pools in triplicate] and urine-based (mean CV, 3.5%; ICC, 99.9%) assays. Reproducibility for the 0.5-mL refined-serum assay was equally good (mean CV, 6.6%; ICC, 99.0%). There was a positive correlation between morning serum melatonin and 6-sulfatoxymelatonin in 24-hour urine (r = 0.46; P = 0.008; n = 49 subjects). Melatonin levels in serum-plasma pairs had a high correlation (r = 0.97; P < 1x10(-4); n = 20 pairs). Morning serum melatonin levels were five times higher than those from the afternoon (before 9 a.m. mean, 11.0 pg/mL, versus after 11 a.m. mean, 2.0 pg/mL). Chinese men had lower melatonin levels (mean, 3.4 pg/mL), whereas Caucasian, African-American, and Ghanaian men had similar levels (mean, 6.7-8.6 pg/mL).These results suggest that melatonin can be detected reliably in serum samples collected in epidemiologic studies in various racial groups.With improved assays, it may be possible to investigate the role of melatonin and the emerging circadian rhythm hypothesis in cancer etiology in epidemiologic studies.

    View details for DOI 10.1158/1055-9965.EPI-10-0004

    View details for Web of Science ID 000278484400008

    View details for PubMedID 20332275

    View details for PubMedCentralID PMC2856692

  • Reproductive factors and risks of biliary tract cancers and stones: a population-based study in Shanghai, China BRITISH JOURNAL OF CANCER Andreotti, G., Hou, L., Gao, Y., Brinton, L. A., Rashid, A., Chen, J., Shen, M., Wang, B., Han, T., Zhang, B., Sakoda, L. C., Fraumeni, J. F., Hsing, A. W. 2010; 102 (7): 1185-1189

    Abstract

    Parity has been linked to gallbladder cancer and gallstones, but the effects of other reproductive factors are less clear.We examined 361 incident biliary tract cancer cases, 647 biliary stone cases, and 586 healthy women in a population-based study in Shanghai.The effects of parity (odds ratios, OR(> or =3 vs 1 child)=2.0, 95% confidence interval (CI) 0.7-5.1), younger age at first birth (OR(per 1-year decrease)=1.2, 95% CI 0.99-1.6), and older age at menarche (OR(per 1-year increase)=1.4, 95% CI 1.1-1.8) on gallbladder cancer risk were more pronounced among women with stones, but the interactions were not significant.Our results provide support for high parity, younger age at first birth, and late age at menarche in the development of gallbladder cancer, particularly among women with biliary stones.

    View details for DOI 10.1038/sj.bjc.6605597

    View details for Web of Science ID 000276159900015

    View details for PubMedID 20216539

    View details for PubMedCentralID PMC2853091

  • Association of 17 Prostate Cancer Susceptibility Loci With Prostate Cancer Risk in Chinese Men PROSTATE Zheng, S. L., Hsing, A. W., Sun, J., Chu, L. W., Yu, K., Li, G., Gao, Z., Kim, S., Isaacs, W. B., Shen, M., Gao, Y., Hoover, R. N., Xu, J. 2010; 70 (4): 425-432

    Abstract

    Several genome-wide association studies (GWAS) in populations of European descent have identified more than a dozen common genetic variants that are associated with prostate cancer risk.To determine whether these variants are also associated with prostate cancer risk in the Chinese population, we evaluated 17 prostate cancer susceptibility loci in a population-based case-control study from Shanghai, including 288 prostate cancer cases and 155 population controls.After adjustment for age, two of the 17 loci were significantly associated with prostate cancer risk, while the other 15 loci were suggestively associated with prostate cancer risk in this population. The strongest associations were found for chromosome 8q24 Region 2 (rs1016343: OR = 2.07, 95% CI: 1.35-3.20, P = 9.4 x 10(-4)) and 8q24 Region 1 (rs10090154: OR = 2.07, 95% CI: 1.31-3.28, P = 0.002); additional single nucleotide polymorphisms (SNPs) assessed in these two 8q24 regions were also significant (OR(Region2) = 1.92-2.05, P = 9.4 x 10(-4) to 0.003, and OR(Region1) = 1.77-1.81, P = 0.01 for all SNPs).Our study shows that multiple prostate cancer risk loci identified in European populations by GWAS are also associated with prostate cancer risk in Chinese men, a low-risk population with mostly clinically relevant cancers. Larger studies in Chinese and Asian populations are needed to confirm these findings and the role of these risk loci in prostate cancer etiology in Asian men.

    View details for DOI 10.1002/pros.21076

    View details for Web of Science ID 000275382600008

    View details for PubMedID 19866473

    View details for PubMedCentralID PMC3078699

  • Finasteride Modifies the Relation between Serum C-Peptide and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial CANCER PREVENTION RESEARCH Neuhouser, M. L., Till, C., Kristal, A., Goodman, P., Hoque, A., Platz, E. A., Hsing, A. W., Albanes, D., Parnes, H. L., Pollak, M. 2010; 3 (3): 279-289

    Abstract

    Hyperinsulinemia and obesity-related metabolic disturbances are common and have been associated with increased cancer risk and poor prognosis. To investigate this issue in relation to prostate cancer, we conducted a nested case-control study within the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial testing finasteride versus placebo for primary prevention of prostate cancer. Cases (n = 1,803) and controls (n = 1,797) were matched on age, PCPT treatment arm, and family history of prostate cancer; controls included all eligible non-whites. Baseline bloods were assayed for serum C-peptide (marker of insulin secretion) and leptin (an adipokine) using ELISA. All outcomes were biopsy determined. Logistic regression calculated odds ratios (OR) for total prostate cancer and polytomous logistic regression calculated ORs for low-grade (Gleason <7) and high-grade (Gleason >7) disease. Results were stratified by PCPT treatment arm for C-peptide. For men on placebo, higher versus lower serum C-peptide was associated with a nearly 2-fold increased risk of high-grade prostate cancer (Gleason >7; multivariate-adjusted OR, 1.88; 95% confidence interval, 1.19-2.97; P(trend) = 0.004). When C-peptide was modeled as a continuous variable, every unit increase in log(C-peptide) resulted in a 39% increased risk of high-grade disease (P = 0.01). In contrast, there was no significant relationship between C-peptide and high-grade prostate cancer among men receiving finasteride. Leptin was not independently associated with high-grade prostate cancer. In conclusion, these results support findings from other observational studies that high serum C-peptide and insulin resistance, but not leptin, are associated with increased risk of high-grade prostate cancer. Our novel finding is that the C-peptide-associated risk was attenuated by use of finasteride.

    View details for DOI 10.1158/1940-6207.CAPR-09-0188

    View details for Web of Science ID 000275159800005

    View details for PubMedID 20179296

    View details for PubMedCentralID PMC3846551

  • Androgen Receptor CAG Repeat Length and Risk of Biliary Tract Cancer and Stones CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Meyer, T. E., O'Brien, T. G., Andreotti, G., Yu, K., Li, Q., Gao, Y., Rashid, A., Shen, M., Wang, B., Han, T., Zhang, B., Niwa, S., Fraumeni, J. F., Hsing, A. W. 2010; 19 (3): 787-793

    Abstract

    Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are rare but highly fatal. Gallstones represent the major risk factor for biliary tract cancer, and share with gallbladder cancer a female predominance and an association with reproductive factors and obesity. Although estrogens have been implicated in earlier studies of gallbladder cancer, there are no data on the role of androgens. Because intracellular androgen activity is mediated through the androgen receptor (AR), we examined associations between AR CAG repeat length [(CAG)(n)] and the risk of biliary tract cancers and stones in a population-based study of 331 incident cancer cases, 837 gallstone cases, and 750 controls from Shanghai, China, where the incidence rates for biliary tract cancer are rising sharply. Men with (CAG)(n) >24 had a significant 2-fold risk of gallbladder cancer [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.07-3.73], relative to those with (CAG)(n) < or = 22. In contrast, women with (CAG)(n) >24 had reduced gallbladder cancer risk (OR, 0.69; 95% CI, 0.43-1.09) relative to those with (CAG)(n) < or = 22; P interaction sex = 0.01, which was most pronounced for women ages 68 to 74 (OR, 0.48; 95% CI, 0.25-0.93; P interaction age = 0.02). No associations were found for bile duct cancer or gallstones. Reasons for the heterogeneity of genetic effects by gender and age are unclear but may reflect an interplay between AR and the levels of androgen as well as estrogen in men and older women. Further studies are needed to confirm these findings and clarify the mechanisms involved.

    View details for DOI 10.1158/1055-9965.EPI-09-0973

    View details for Web of Science ID 000278475300019

    View details for PubMedID 20200439

    View details for PubMedCentralID PMC2837546

  • Human Papillomavirus Types 16, 18, and 31 Serostatus and Prostate Cancer Risk in the Prostate Cancer Prevention Trial CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sutcliffe, S., Viscidi, R. P., Till, C., Goodman, P. J., Hoque, A. M., Hsing, A. W., Thompson, I. M., Zenilman, J. M., De Marzo, A. M., Platz, E. A. 2010; 19 (2): 614-618

    Abstract

    Since human papillomavirus (HPV) infection was first identified as a risk factor for cervical cancer, several seroepidemiologic and tissue-based studies have investigated HPV in relation to prostate cancer, another common genitourinary malignancy, with mixed results. To further inform this potential association, we conducted a large, prospective investigation of HPV types 16, 18, and 31 in relation to risk of prostate cancer in the Prostate Cancer Prevention Trial. Cases were a sample of men diagnosed with prostate cancer after visit 2 or on their end-of-study biopsy (n = 616). Controls were men not diagnosed with prostate cancer during the trial or on their end-of-study biopsy (n = 616). Controls were frequency matched to cases by age, treatment arm, and family history of prostate cancer. Sera from visit 2 were tested for IgG antibodies against HPV types 16, 18, and 31. No associations were observed for weak or strong HPV-16 [odds ratio (OR), 0.94; 95% confidence interval (95% CI), 0.53-1.64 and OR, 1.07; 95% CI, 077-1.48, respectively], HPV-18 (OR, 0.75; 95% CI, 0.27-2.04 and OR, 0.87; 95% CI, 0.47-1.63, respectively), or HPV-31 seropositivity (OR, 0.76; 95% CI, 0.45-1.28 and OR, 1.15; 95% CI, 0.80-1.64, respectively) and risk of prostate cancer. Considering this finding in the context of the HPV and prostate cancer literature, HPV does not appear to be associated with risk of prostate cancer, at least by mechanisms proposed to date, and using epidemiologic designs and laboratory techniques currently available.

    View details for DOI 10.1158/1055-9965.EPI-09-1080

    View details for Web of Science ID 000278403900036

    View details for PubMedID 20142255

    View details for PubMedCentralID PMC2820385

  • Genetic determinants of serum lipid levels in Chinese subjects: a population-based study in Shanghai, China EUROPEAN JOURNAL OF EPIDEMIOLOGY Andreotti, G., Menashe, I., Chen, J., Chang, S., Rashid, A., Gao, Y., Han, T., Sakoda, L. C., Chanock, S., Rosenberg, P. S., Hsing, A. W. 2009; 24 (12): 763-774

    Abstract

    We examined the associations between 21 single nucleotide polymorphisms (SNPs) of eight lipid metabolism genes and lipid levels in a Chinese population. This study was conducted as part of a population-based study in China with 799 randomly selected healthy residents who provided fasting blood and an in-person interview. Associations between variants and mean lipid levels were examined using a test of trend and least squares mean test in a general linear model. Four SNPs were associated with lipid levels: LDLR rs1003723 was associated with total cholesterol (P-trend = 0.002) and LDL (P-trend = 0.01), LDLR rs6413503 was associated with total cholesterol (P-trend = 0.05), APOB rs1367117 was associated with apoB (P-trend = 0.02), and ABCB11 rs49550 was associated with total cholesterol (P-trend = 0.01), triglycerides (P-trend = 0.01), and apoA (P-trend = 0.01). We found statistically significant effects on lipid levels for LDLR rs6413503 among those with high dairy intake, LPL rs263 among those with high allium vegetable intake, and APOE rs440446 among those with high red meat intake. We identified new associations between SNPs and lipid levels in Chinese previously found in Caucasians. These findings provide insight into the role of lipid metabolism genes, as well as the mechanisms by which these genes may be linked with disease.

    View details for DOI 10.1007/s10654-009-9402-3

    View details for Web of Science ID 000272615500008

    View details for PubMedID 19888660

    View details for PubMedCentralID PMC2885778

  • Trichomonosis and subsequent risk of prostate cancer in the Prostate Cancer Prevention Trial INTERNATIONAL JOURNAL OF CANCER Sutcliffe, S., Alderete, J. F., Till, C., Goodman, P. J., Hsing, A. W., Zenilman, J. M., De Marzo, A. M., Platz, E. A. 2009; 124 (9): 2082-2087

    Abstract

    We previously observed a positive association between a history of trichomonosis, a sexually transmitted infection caused by the protozoan, Trichomonas vaginalis, and prostate cancer risk in the Health Professionals Follow-up Study. To determine the reproducibility of this finding, we conducted a second, prospective investigation of trichomonosis and prostate cancer in the Prostate Cancer Prevention Trial. Participants were men (>or=55 years of age) with no evidence of prostate cancer at enrollment (n = 18,882). Men were screened annually for prostate cancer, and if not diagnosed during the trial, were offered an end-of-study prostate biopsy. Cases were a sample of men diagnosed with prostate cancer on any biopsy after visit 2 or on their end-of-study biopsy (n = 616). Controls were men not diagnosed with prostate cancer during the trial or on their end-of-study biopsy (n = 616). Controls were frequency-matched to cases by age, treatment arm, and family history of prostate cancer. Serum from visit 2 was tested for anti-T. vaginalis IgG antibodies. No association was observed between T. vaginalis serostatus and prostate cancer. 21.5% of cases and 24.8% of controls had low seropositivity, and 15.2% and 15.0% had high seropositivity. Compared to seronegative men, the odds ratio of prostate cancer for men with low seropositivity was 0.83 [95% confidence interval (CI): 0.63-1.09), and that for men with high seropositivity was 0.97 (95% CI: 0.70-1.34). Given the original strong biologic rationale and potential for prevention, additional studies are warranted to help resolve discrepancies between study findings and to further investigate this hypothesis from a variety of different approaches.

    View details for DOI 10.1002/ijc.24144

    View details for Web of Science ID 000264647600011

    View details for PubMedID 19117055

    View details for PubMedCentralID PMC2682694

  • Variants in hormone-related genes and the risk of biliary tract cancers and stones: a population-based study in China CARCINOGENESIS Park, S. K., Andreotti, G., Sakoda, L. C., Gao, Y., Rashid, A., Chen, J., Chen, B. E., Rosenberg, P. S., Shen, M., Wang, B., Han, T., Zhang, B., Yeager, M., Chanock, S., Hsing, A. W. 2009; 30 (4): 606-614

    Abstract

    Biliary tract cancers, encompassing gallbladder, extrahepatic bile duct and ampulla of Vater cancers, are uncommon but often fatal malignancies. Hormone-related factors, including parity, oral contraceptive use, obesity, and gallstones, have been implicated in the etiology of these cancers. To further clarify the role of hormones in biliary tract cancers and biliary stones, we genotyped 18 single-nucleotide polymorphisms (SNPs) in nine genes involved in steroid hormone biosynthesis, metabolism and transport in a population-based case-control study in Shanghai, China. This study included subjects who completed an interview and provided blood, which totaled 411 biliary tract cancer and 893 biliary stone patients and 786 healthy Shanghai residents. The CYP1A1 IVS1 + 606 (rs2606345) T allele was associated with gallbladder [odds ratio (OR) = 2.0, 95% confidence interval (CI), 1.3-3.0] and bile duct cancers (OR = 1.8, 95% CI = 1.1-3.1), whereas the CYP1A1 Ex7 + 131 (rs1048943) G allele was associated with ampulla of Vater cancer (OR = 2.9, 95% CI = 1.5-5.4). After taking into account multiple comparisons for SNPs within each gene, CYP1A1 was significantly associated with gallbladder (P = 0.004) and ampulla of Vater cancers (P = 0.01), but borderline with bile duct cancer (P = 0.06). The effect of CYP1A1 IVS1 + 606 on gallbladder cancer was more pronounced among non-obese (body mass index < 23) (OR = 3.3, 95% CI = 1.8-6.1; P interaction = 0.001). Among women taking oral contraceptives, the effect of SHBG Ex8 + 6 (rs6259) on gallbladder cancer (OR = 6.7, 95% CI = 2.2-20.5; P interaction = 0.001) and stones (OR = 2.3, 95% CI = 1.1-4.9; P-interaction = 0.05) was statistically significant. Our findings suggest that common variants in hormone-related genes contribute to the risk of biliary tract cancers and stones, possibly by modulating hormone metabolism.

    View details for DOI 10.1093/carcin/bgp024

    View details for Web of Science ID 000264889100008

    View details for PubMedID 19168589

    View details for PubMedCentralID PMC2664453

  • Diabetes mellitus and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial CANCER CAUSES & CONTROL Leitzmann, M. F., Ahn, J., Albanes, D., Hsing, A. W., Schatzkin, A., Chang, S., Huang, W., Weiss, J. M., Danforth, K. N., Grubb, R. L., Andriole, G. L. 2008; 19 (10): 1267-1276

    Abstract

    A history of diabetes has been fairly consistently related to a reduced prostate cancer risk, but previous investigations have not always addressed whether the relation with diabetes varies by prostate cancer aggressiveness or the association between diabetes and prostate cancer is modified by physical activity level and body mass, variables closely related to glucose metabolism.We prospectively examined the diabetes-prostate cancer risk relationship among 33,088 men in the screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.During 8.9 years follow-up, we ascertained 2,058 incident prostate cancer cases. Diabetes history was related to decreased risk of total prostate cancer (RR = 0.80, 95% CI = 0.68-0.95). The apparent protection afforded by diabetes was primarily due to the inverse relation with non-aggressive disease (i.e., the combination of low grade (Gleason sum <8) and low stage (clinical stages I or II); RR = 0.75; 95% CI = 0.62-0.91). In contrast, no association was noted between diabetes and aggressive disease (i.e., high grade or high stage (Gleason sum >or=8 or clinical stages III or IV); RR = 1.04, 95% CI = 0.74-1.45). In further analyses, the association between diabetes and aggressive prostate cancer was suggestively positive for men who were lean (RR = 1.64, 95% CI = 0.87-3.07; BMI < 25 kg/m(2)) and it was positive for men who were the most physically active (RR = 1.63; 95% CI = 1.07-2.62; 3+ hours vigorous activity/week). By comparison, no relations of diabetes to aggressive prostate cancer were noted for their heavier or physically less active counterparts (p-value for tests of interaction = 0.10 and 0.03 BMI and physical activity, respectively).In this study, diabetes showed divergent relations with prostate cancer by tumor aggressiveness. Specifically, diabetes was inversely associated with early stage prostate cancer but it showed no relation with aggressive prostate cancer. Exploratory analyses suggested a positive association between diabetes and aggressive prostate cancer in the subgroup of men with a low BMI.

    View details for DOI 10.1007/s10552-008-9198-6

    View details for Web of Science ID 000260766300028

    View details for PubMedID 18618278

  • Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer risk INTERNATIONAL JOURNAL OF CANCER Stevens, V. L., Hsing, A. W., Talbot, J. T., Zheng, S. L., Sun, J., Chen, J., Thun, M. J., Xu, J., Calle, E. E., Rodriguez, C. 2008; 123 (11): 2644-2650

    Abstract

    Toll-like receptors (TLRs) are key players in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. The proposed role of chronic inflammation in prostate carcinogenesis has prompted investigation into the association of common genetic variation in TLRs with the risk of this cancer. We investigated the role of common SNPs in a gene cluster encoding the TLR10, TLR6 and TLR1 proteins in prostate cancer etiology among 1,414 cancer cases and 1,414 matched controls from the Cancer Prevention Study II Nutrition Cohort. Twenty-eight SNPs, which included the majority of the common nonsynonymous SNPs in the 54-kb gene region and haplotype-tagging SNPs that defined 5 specific haplotype blocks, were genotyped and their association with prostate cancer risk determined. Two SNPs in TLR10 [I369L (rs11096955) and N241H (rs11096957)] and 4 SNPs in TLR1 [N248S (rs4833095), S26L (rs5743596), rs5743595 and rs5743551] were associated with a statistically significant reduced risk of prostate cancer of 29-38% (for the homozygous variant genotype). The association of these SNPs was similar when the analysis was limited to cases with advanced prostate cancer. Haplotype analysis and linkage disequilibrium findings revealed that the 6 associated SNPs were not independent and represent a single association with reduced prostate cancer risk (OR = 0.55, 95% CI: 0.33, 0.90). Our study suggest that a common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations.

    View details for DOI 10.1002/ijc.23826

    View details for Web of Science ID 000260844100021

    View details for PubMedID 18752252

  • Variants in circadian genes and prostate cancer risk: a population-based study in China PROSTATE CANCER AND PROSTATIC DISEASES Chu, L. W., Zhu, Y., Yu, K., Zheng, T., Yu, H., Zhang, Y., Sesterhenn, I., Chokkalingam, A. P., Danforth, K. N., Shen, M., Stanczyk, F. Z., Gao, Y., Hsing, A. W. 2008; 11 (4): 342-348

    Abstract

    Circadian genes influence a variety of biological processes that are important in prostate tumorigenesis including metabolism. To determine if variants in circadian genes alter prostate cancer risk, we genotyped five variants in five circadian genes in a population-based case-control study conducted in China (187 cases and 242 controls). These variants included CRY2 rs1401417:G>C, CSNK1E rs1005473:A>C, NPAS2 rs2305160:G>A, PER1 rs2585405:G>C and PER3 54-bp repeat length variant. Men with the cryptochrome 2 (CRY2)-variant C allele had a significant 1.7-fold increased prostate cancer risk (95% confidence interval (CI), 1.1-2.7) relative to those with the GG genotype. This risk increased to 4.1-fold (95% CI, 2.2-8.0) in men who also had greater insulin resistance (IR) as compared to men with the GG genotype and less IR. In contrast, among men with less IR, the NPAS2-variant A allele was associated with decreased prostate cancer risk (odds ratio=0.5, 95% CI, 0.3-1.0) as compared to the GG genotype. Our findings, although in need of confirmation, suggest that variations in circadian genes may alter prostate cancer risk and some biological processes may modify this effect.

    View details for DOI 10.1038/sj.pcan.4501024

    View details for Web of Science ID 000260751100006

    View details for PubMedID 17984998

  • Correlation between Circadian Gene Variants and Serum Levels of Sex Steroids and Insulin-like Growth Factor-I CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chu, L. W., Zhu, Y., Yu, K., Zheng, T., Chokkalingam, A. P., Stanczyk, F. Z., Gao, Y., Hsing, A. W. 2008; 17 (11): 3268-3273

    Abstract

    A variety of biological processes, including steroid hormone secretion, have circadian rhythms, which are influenced by nine known circadian genes. Previously, we reported that certain variants in circadian genes were associated with risk for prostate cancer. To provide some biological insight into these findings, we examined the relationship of five variants of circadian genes, including NPAS2 (rs2305160:G > A), PER1 (rs2585405:G > C), CSNK1E (rs1005473:A > C), PER3 (54-bp repeat length variant), and CRY2 (rs1401417:G > C), with serum levels of sex steroids and insulin-like growth factor (IGF)-I and IGF-binding protein 3 (IGFBP3) in 241 healthy elderly Chinese men (mean age of 71.5). Age-adjusted and waist-to-hip ratio-adjusted ANOVA followed by likelihood ratio tests (LRT) showed that the NPAS2 variant A allele was associated with lower free and bioavailable testosterone (P(LRT) = 0.02 and 0.01, respectively) compared with the GG genotype. In addition, the PER1 variant was associated with higher serum levels of sex hormone-binding globulin levels (Ptrend = 0.03), decreasing 5alpha-androstane-3alpha, 17beta-diol glucuronide levels (Ptrend = 0.02), and decreasing IGFBP3 levels (Ptrend = 0.05). Furthermore, the CSNK1E variant C allele was associated with higher testosterone to dihydrotestosterone ratios (P(LRT) = 0.01) compared with the AA genotype, whereas the longer PER3 repeat was associated with higher serum levels of IGF-I (P(LRT) = 0.03) and IGF-I to IGFBP3 ratios (P(LRT) = 0.04). The CRY2 polymorphism was not associated with any biomarkers analyzed. Our findings, although in need of confirmation, suggest that variations in circadian genes are associated with serum hormone levels, providing biological support for the role of circadian genes in hormone-related cancers.

    View details for DOI 10.1158/1055-9965.EPI-08-0073

    View details for Web of Science ID 000260896500048

    View details for PubMedID 18990770

  • Insulin-like growth factors, their binding proteins, and prostate cancer risk: Analysis of individual patient data from 12 prospective studies ANNALS OF INTERNAL MEDICINE Roddam, A. W., Allen, N. E., Appleby, P., Key, T. J., Ferrucci, L., Carter, H. B., Metter, E. J., Chen, C., Weiss, N. S., Fitzpatrick, A., Hsing, A. W., Lacey, J. V., Helzlsouer, K., Rinaldi, S., Riboli, E., Kaaks, R., Janssen, J. A., Wildhagen, M. F., Schroeder, F. H., Platz, E. A., Pollak, M., Giovannucci, E., Schaefer, C., Quesenberry, C. P., Vogelman, J. H., Severi, G., English, D. R., Giles, G. G., Stattin, P., Hallmans, G., Johansson, M., Chan, J. M., Gann, P., Oliver, S. E., Holly, J. M., Donovan, J., Meyer, F., Bairati, I., Galan, P. 2008; 149 (7): 461-W88

    Abstract

    Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer.To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer.Studies identified in PubMed, Web of Science, and CancerLit.The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate.Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom.The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake.Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies.High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

    View details for Web of Science ID 000260004400003

    View details for PubMedID 18838726

    View details for PubMedCentralID PMC2584869

  • Androgen and prostate cancer: Is the hypothesis dead? CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hsing, A. W., Chu, L. W., Stanczyk, F. Z. 2008; 17 (10): 2525-2530

    Abstract

    Data from animal, clinical, and prevention studies support the role of androgen in prostate cancer growth, proliferation, and progression. However, results serum-based epidemiologic studies in humans have been inconclusive. Part of the inconsistency in these findings stems from differences in study population, assay accuracy, intraperson variation, and limited sample size. Recently, data from a large pooled analysis of 18 prospective studies (3,886 cases and 6,438 healthy controls) showed no association between serum androgen and prostate cancer risk. It is not surprising that the pooled analysis did not find a positive link between circulating levels of total testosterone and prostate cancer risk because, individually, few of the 18 studies included in the pooled analysis reported a substantial positive association. The null result, however, does not pronounce a death sentence for the androgen hypothesis; rather, it underscores the importance of a better understanding of androgen action within the prostate, including the relationship between tissue and serum levels of androgen. In this commentary, we explain why circulating levels of testosterone may not reflect androgen action in the prostate and why tissue levels of androgen, in particular dihydrotestosterone, and the androgen receptor and its coregulators are critical to androgen action in the prostate and should be incorporated in future studies. It is timely to integrate system thinking into our research and use an interdisciplinary approach that involves different disciplines, including epidemiology, endocrinology, pathology, and molecular biology, to help dissect the complex interplay between sex steroids and genetic and lifestyle factors in prostate cancer etiology.

    View details for DOI 10.1158/1055-9965.EPI-08-0448

    View details for Web of Science ID 000260051000002

    View details for PubMedID 18842992

  • Variants of DNA repair genes and the risk of biliary tract cancers and stones: A populaton-based study in China CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Zhang, M., Huang, W., Andreotti, G., Gao, Y., Rashid, A., Chen, J., Sakoda, L. C., Shen, M., Wang, B., Chanock, S., Hsing, A. W. 2008; 17 (8): 2123-2127

    Abstract

    Biliary tract cancers, which encompass tumors of the gallbladder, extrahepatic ducts, and ampulla of Vater, are relatively rare tumors with a high fatality rate. Other than a close link with gallstones, the etiology of biliary tract cancers is poorly understood. We conducted a population-based case-control study in Shanghai, China, to examine whether genetic variants in several DNA repair genes are associated with biliary tract cancers or biliary stones. Genomic DNA from 410 patients with biliary tract cancers (236 gallbladder, 127 bile duct, and 47 ampulla of Vater), 891 patients with biliary stones, and 786 healthy subjects randomly selected from the Shanghai population were genotyped for putative functional single nucleotide polymorphisms in four DNA repair genes (MGMT, RAD23B, CCNH, and XRCC3). Of the five single nucleotide polymorphisms examined, only one (MGMT EX5-25C>T, rs12917) was associated with biliary tract cancer. Independent of gallstones, subjects carrying the CT genotype of the MGMT EX5-25C>T marker had a significantly reduced risk of gallbladder cancer [odds ratio (OR), 0.63; 95% confidence interval (95% CI), 0.41-0.97; P = 0.02] and nonsignificant reduced risks of bile duct (OR, 0.61; 95% CI, 0.35-1.06) and ampulla of Vater (OR, 0.85; 95% CI, 0.39-1.87) cancers. However, this marker was not associated with biliary stones, and the other markers examined were not significantly associated with either biliary tract cancers or stones. Findings from this population-based study in Shanghai suggest that MGMT gene variants may alter susceptibility to biliary tract cancer, particularly gallbladder cancer. Confirmation in future studies, however, is required.

    View details for DOI 10.1158/1055-9965.EPI-07-2735

    View details for Web of Science ID 000258800800041

    View details for PubMedID 18708406

    View details for PubMedCentralID PMC2860746

  • Variants in inflammation genes and the risk of biliary tract cancers and stones: A population-based study in China CANCER RESEARCH Hsing, A. W., Sakoda, L. C., Rashid, A., Andreotti, G., Chen, J., Wang, B., Shen, M., Chen, B. E., Rosenberg, P. S., Zhang, M., Niwa, S., Chu, L., Welch, R., Yeager, M., Fraumeni, J. F., Gao, Y., Chanock, S. J. 2008; 68 (15): 6442-6452

    Abstract

    To evaluate the role of chronic inflammation in the development of gallstones and biliary tract cancer, we examined the risk associated with 62 single nucleotide polymorphisms (SNPs), in 22 inflammation-related genes, in a population-based case-control study conducted in Shanghai, China, where the incidence of biliary tract cancer has been increasing in recent decades. The study included 411 cases with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater), 895 with biliary stones, and 786 controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association of individual SNPs and haplotypes with biliary stones and biliary tract cancer. Of the 62 SNPs examined, 14 were related to the risk of biliary cancer and stones. Specifically, variants in the IL8, IL8RB, RNASEL, and NOS2 genes were associated with biliary stones, whereas VEGF variants were associated with gallbladder cancer. Of the 10 genes with multiple SNPs from which we inferred haplotypes, only one IL8RB haplotype, consisting of 3 SNPs (rs2230054, rs1126579, and rs1126580), was associated with the risk of bile duct cancer (P = 0.003) and biliary stones (P = 0.02), relative to the most frequent haplotype. In summary, common variants in genes that influence inflammatory responses may predispose to gallstones and biliary tract cancer, suggesting the need for future studies into the immunologic and inflammatory pathways that contribute to biliary diseases, including cancer.

    View details for DOI 10.1158/0008-5472.CAN-08-0444

    View details for Web of Science ID 000258177600050

    View details for PubMedID 18676870

    View details for PubMedCentralID PMC2860726

  • Body size and the risk of biliary tract cancer: a population-based study in China BRITISH JOURNAL OF CANCER Hsing, A. W., Sakoda, L. C., Rashid, A., Chen, J., Shen, M. C., Han, T. Q., Wang, B. S., Gao, Y. T. 2008; 99 (5): 811-815

    Abstract

    Though obesity is an established risk factor for gall bladder cancer, its role in cancers of the extrahepatic bile ducts and ampulla of Vater is less clear, as also is the role of abdominal obesity. In a population-based case-control study of biliary tract cancer in Shanghai, China, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for biliary tract cancer in relation to anthropometric measures, including body mass index (BMI) at various ages and waist-to-hip ratio (WHR), adjusting for age, sex, and education. The study included 627 patients with biliary tract cancer (368 gall bladder, 191 bile duct, 68 ampulla of Vater) and 959 healthy subjects randomly selected from the population. A higher BMI at all ages, including early adulthood (ages 20-29 years), and a greater WHR were associated with an increased risk of gall bladder cancer. A high usual adult BMI (>or=25) was associated with a 1.6-fold risk of gall bladder cancer (95% CI 1.2-2.1, P for trend <0.001). Among subjects without gallstones, BMI was also positively associated with gall bladder cancer risk. Regardless of BMI levels, increasing WHR was associated with an excess risk of gall bladder cancer risk, with those having a high BMI (>or=25) and a high WHR (>0.90) having the highest risk of gall bladder cancer (OR=12.6, 95% CI 4.8-33.2), relative to those with a low BMI and WHR. We found no clear risk patterns for cancers of the bile duct and ampulla of Vater. These results suggest that both overall and abdominal obesity, including obesity in early adulthood, are associated with an increased risk of gall bladder cancer. The increasing prevalence of obesity and cholesterol stones in Shanghai seems at least partly responsible for the rising incidence of gall bladder cancer in Shanghai.

    View details for DOI 10.1038/sj.bjc.6604616

    View details for Web of Science ID 000258720100021

    View details for PubMedID 18728671

    View details for PubMedCentralID PMC2528141

  • Androgens and the molecular epidemiology of prostate cancer CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY Chu, L. W., Reichardt, J. K., Hsing, A. W. 2008; 15 (3): 261-270

    Abstract

    Despite clinical and experimental evidence that show androgens are important in prostate carcinogenesis, epidemiologic studies of serum androgens have been inconclusive. In this review, we summarize the current state of the literature and provide insights and direction for epidemiologic research on androgens and prostate cancer.To date, data on serum androgens in prostate cancer remain inconclusive. Large studies on variants in some androgen-metabolizing genes [SRD5A2, CYP17A1, and hydroxysteroid dehydrogenase (HSD)17B1] do not show a convincing links to prostate cancer, though there are insufficient data to draw conclusions on other genes related to androgen metabolism, including UDP-glycosyltransferases (UGT), sulfotransferases (SULT), CYP3A, and estrogen-related genes. There is some evidence, although controversial, suggesting that select variants may confer risk to certain subtypes of prostate cancer. The most notable finding in 2007 is the highly reproducible link between the chromosome 8q24 risk region and prostate cancer susceptibility.Besides the link between the 8q24 region and prostate cancer risk, population studies do not convincingly show that polymorphisms in androgen metabolism genes are associated with prostate cancer risk. Large epidemiologic studies with comprehensive gene coverage and reliable exposure data are needed to clarify further the role of androgens and their related genes in prostate cancer.

    View details for DOI 10.1097/MED.0b013e3282febcf6

    View details for Web of Science ID 000207754800008

    View details for PubMedID 18438175

  • Serum lipid levels and the risk of biliary tract cancers and biliary stones: A population-based study in China INTERNATIONAL JOURNAL OF CANCER Andreotti, G., Chen, J., Gao, Y., Rashid, A., Chang, S., Shen, M., Wang, B., Han, T., Zhang, B., Danforth, K. N., Althuis, M. D., Hsing, A. W. 2008; 122 (10): 2322-2329

    Abstract

    Biliary tract cancers, encompassing the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Gallstones, the predominant risk factor for biliary cancers, are linked with hyperlipidemia. As part of a population-based case-control study conducted in Shanghai, China, we examined the associations of serum lipid levels with biliary stones and cancers. We included 460 biliary cancer cases (264 gallbladder, 141 extrahepatic bile duct, and 55 ampulla of Vater), 981 biliary stone cases and 858 healthy individuals randomly selected from the population. Participants completed an in-person interview and gave overnight fasting blood samples. Participants in the highest quintile of triglycerides (>/=160 mg/dl) had a 1.4-fold risk of biliary stones (95% CI = 1.1-1.9), a 1.9-fold risk of gallbladder cancer (95% CI = 1.3-2.8), and a 4.8-fold risk of bile duct cancer (95% CI = 2.8-8.1), compared to the reference group (third quintile: 90-124 mg/dl). Participants in the lowest quintile of high-density lipoprotein (HDL) (<30 mg/dl) had a 4.2-fold risk of biliary stones (95% CI = 3.0-6.0), an 11.6-fold risk of gallbladder cancer (95% CI = 7.3-18.5), and a 16.8-fold risk of bile duct cancer (95% CI = 9.1-30.9), relative to the reference group (third quintile: 40-49 mg/dl). In addition, total cholesterol, low-density lipoprotein (LDL) and apolipoprotein A (apo A) were inversely associated with biliary stones; whereas low levels as well as high levels of total cholesterol, LDL, apo A and apolipoprotein B (apo B) were associated with excess risks of biliary tract cancers. Our findings support a role for serum lipids in gallstone development and biliary carcinogenesis.

    View details for DOI 10.1002/ijc.23307

    View details for Web of Science ID 000254983100020

    View details for PubMedID 18076041

    View details for PubMedCentralID PMC2860727

  • Endogenous sex hormones and the risk of prostate cancer: A prospective study INTERNATIONAL JOURNAL OF CANCER Weiss, J. M., Huang, W., Rinaldi, S., Fears, T. R., Chatterjee, N., Hsing, A. W., Crawford, E. D., Andriole, G. L., Kaaks, R., Hayes, R. B. 2008; 122 (10): 2345-2350

    Abstract

    Sex steroid hormones influence prostate development and maintenance through their roles in prostate cellular proliferation, differentiation and apoptosis. Although suspected to be involved in prostate carcinogenesis, an association between circulating androgens and prostate cancer has not been clearly established in epidemiologic studies. We conducted a nested case-control study with prospectively collected samples in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to examine associations of prostate cancer with androstenedione (Delta4-A), testosterone (T), sex hormone-binding globulin (SHBG) and 3alpha-androstanediol glucuronide (3alpha-diolG). A total of 727 incident Caucasian prostate cancer cases (age >/= 65 years, N = 396) and 889 matched controls were selected for this analysis. Overall, prostate cancer risks were unrelated to serum T, estimated free and bioavailable T, and SHBG; however, risks increased with increasing T:SHBG ratio (p(trend) = 0.01), mostly related to risk in older men (>/=65 years, p(trend) = 0.001), particularly for aggressive disease [highest versus lowest quartile: odds ratio (OR) 2.76, 95% confidence interval (CI) 1.50-5.09]. No clear patterns were noted for Delta4-A and 3alpha-diolG. In summary, our large prospective study did not show convincing evidence of a relationship between serum sex hormones and prostate cancer. T:SHBG ratio was related to risk in this older population of men, but the significance of this ratio in steroidal biology is unclear. (c) 2008 Wiley-Liss, Inc.

    View details for DOI 10.1002/ijc.23326

    View details for Web of Science ID 000254983100023

    View details for PubMedID 18172860

  • Polymorphism of genes related to insulin sensitivity and the risk of biliary tract cancer and biliary stone: a population-based case-control study in Shanghai, China CARCINOGENESIS Chang, S., Rashid, A., Gao, Y., Andreotti, G., Shen, M., Wang, B., Han, T., Zhang, B., Sakoda, L. C., Leitzmann, M. F., Chen, B. E., Rosenberg, P. S., Chen, J., Chanock, S. J., Hsing, A. W. 2008; 29 (5): 944-948

    Abstract

    Biliary tract cancer, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, is a rare but highly fatal malignancy. Obesity and gallstones, both related to insulin resistance, are linked to an elevated risk of biliary cancer. The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs), expressed in adipose tissue, play a key role in the regulation of obesity-related insulin sensitivity, thus genetic variants of these two receptor genes may be related to biliary cancer and stones. We examined the associations of seven single-nucleotide polymorphisms in the PPAR-gamma, PPAR-delta, RXR-alpha, RXR-beta and INS genes with biliary cancer and stones in a population-based case-control study in Shanghai, China. We included 237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater cancer cases, 895 stone cases and 786 population controls. Relative to individuals with the RXR-beta C51T (rs2076310) CC genotype, those having the TT genotype had a 1.6-fold risk for bile duct cancer [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 0.99-2.84], with a more pronounced association among men (OR = 2.30; 95% CI = 1.14-4.65; P interaction = 0.07). This marker was also associated with a higher risk of gallstones among subjects with a higher body mass index (BMI) (>or=23 kg/m(2)) (OR = 1.80; 95% CI = 1.09-2.94), although the interaction with BMI was not statistically significant (P interaction = 0.28). No association was found between other variants and biliary cancers and stones. Results from this population-based study suggest that certain genetic variants involved in the regulation of obesity-related insulin sensitivity may increase susceptibility to bile duct cancer and gallstones.

    View details for DOI 10.1093/carcin/bgn025

    View details for Web of Science ID 000257576600011

    View details for PubMedID 18375961

    View details for PubMedCentralID PMC2443392

  • Hepatitis B and C virus infection and the risk of biliary tract cancer: A population-based study in China INTERNATIONAL JOURNAL OF CANCER Hsing, A. W., Zhang, M., Rashid, A., McGlynn, K. A., Wang, B., Niwa, S., Ortiz-Conde, B. A., Goedert, J. J., Fraumeni, J. F., O'Brien, T. R., Gao, Y. 2008; 122 (8): 1849-1853

    Abstract

    Emerging data suggest that chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections may also play a role in extrahepatic bile duct cancers. To test the HBV hypothesis, we examined the relationship of HBV/HCV infection with risks of biliary tract cancer and biliary stones in a population-based case-control study conducted in Shanghai, China. Standard assays were used to detect HBV surface antigen (HBsAg) and antibodies against HBV core antigen (anti-HBc) and hepatitis C virus (anti-HCV) in sera from 417 patients with biliary tract cancers, 517 with biliary stones, and 762 healthy controls randomly selected from the population. Unconditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for each disease type. HBsAg seroprevalence was 7.3% among population controls and 14.2% among patients with extrahepatic bile duct cancer, resulting in a 2.4-fold risk of extrahepatic bile duct cancer (95% CI 1.2-4.5). No association was found for cancers of the gallbladder (prevalence 8.2%) or the ampulla of Vater (6.1%), or for stones in the gallbladder (10.1%) or bile duct (9.3%). Further adjustment for education, smoking, body mass index, diabetes and gallstones did not materially change the results. Prevalence of HCV infection in this population was low (2%), limiting our ability to detect an association with biliary diseases. In Shanghai, an HBV endemic area, chronic HBV infection was associated with a 2.4-fold risk of extrahepatic bile duct cancer. These results should be confirmed in other populations with varying risks of HBV and HCV infection.

    View details for DOI 10.1002/ijc.23251

    View details for Web of Science ID 000254068300024

    View details for PubMedID 18076042

  • Polymorphisms in angogenesis-related genes and prostate cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Jacobs, E. J., Hsing, A. W., Bain, E. B., Stevens, V. L., Wang, Y., Chen, J., Chanock, S. J., Zheng, S. L., Xu, J., Thun, M. J., Calle, E. E., Rodriguezi, C. 2008; 17 (4): 972-977

    Abstract

    Angiogenesis is required for development and progression of prostate cancer. Potentially functional single nucleotide polymorphisms (SNP) in genes important in prostate angiogenesis (VEGF, HIF1A, and NOS3) have previously been associated with risk or severity of prostate cancer.Prostate cancer cases (n = 1,425) and controls (n = 1,453) were selected from the Cancer Prevention Study II Nutrition Cohort. We examined associations between 58 SNPs in nine angiogenesis-related candidate genes (EGF, LTA, HIF1A, HIF1AN, MMP2, MMP9, NOS2A, NOS3, VEGF) and risk of overall and advanced prostate cancer. Unconditional logistic regression was used to estimate odds ratios, adjusted for matching factors.Our results did not replicate previously observed associations with SNPs in VEGF, HIF1A, or NOS3, nor did we observe associations with SNPs in EGF, LTA, HIF1AN, MMP9, or NOS2A. In the MMP2 gene, three intronic SNPs, all in linkage disequilibrium, were associated with overall and advanced prostate cancer (for overall prostate cancer, P(trend) = 0.01 for rs1477017, P(trend) = 0.01 for rs17301608, P(trend) = 0.02 for rs11639960). However, two of these SNPs (rs17301608 and rs11639960) were examined and were not associated with prostate cancer in a recent genome-wide association study using prostate cancer cases and controls from the Prostate, Lung, Colorectal, and Ovary study cohort. Furthermore, when we pooled our results for these two SNPs with those from the Prostate, Lung, Colorectal, and Ovary cohort; neither SNP was associated with prostate cancer.None of the SNPs examined seem likely to be importantly associated with risk of overall or advanced prostate cancer.

    View details for DOI 10.1158/1055-9965.EPI-07-2787

    View details for Web of Science ID 000254969000032

    View details for PubMedID 18398039

  • Polymorphic variants in PTGS2 and prostate cancer risk: results from two large nested case-control studies CARCINOGENESIS Danforth, K. N., Hayes, R. B., Rodriguez, C., Yu, K., Sakoda, L. C., Huang, W., Chen, B. E., Chen, J., Andriole, G. L., Calle, E. E., Jacobs, E. J., Chu, L. W., Figueroa, J. D., Yeager, M., Platz, E. A., Michaud, D. S., Chanock, S. J., Thun, M. J., Hsing, A. W. 2008; 29 (3): 568-572

    Abstract

    Chronic inflammation has been hypothesized to increase prostate cancer risk. Prostaglandin-endoperoxide synthase 2 (PTGS2) encodes the proinflammatory cyclooxygenase 2 enzyme believed to be the rate-limiting step in the synthesis of prostaglandins, important mediators of inflammation. We investigated associations between PTGS2 polymorphisms and prostate cancer risk among 2321 prostate cancer cases and 2560 controls in two large case-control studies nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the Cancer Prevention Study II Nutrition Cohort. Five single nucleotide polymorphisms (SNPs) (rs5277, rs20432, rs4648276, rs5275 and rs689470) were examined in SNP and haplotype analyses (five SNPs in PLCO and four SNPs in the Nutrition Cohort). In PLCO, the Ex10 +837 T>C marker (rs5275) was initially associated with prostate cancer risk (P-trend = 0.02) but became non-significant after adjustment for multiple comparisons (P = 0.08); this SNP showed no association with prostate cancer risk in the Nutrition Cohort (P-trend = 0.54) or in an analysis pooling the two cohorts (P-trend = 0.20). No other SNP was associated with prostate cancer risk in PLCO or the Nutrition Cohort individually or combined. Haplotype analyses suggested an association between PTGS2 variants in PLCO alone (global P = 0.007), but not in the Nutrition Cohort (global P = 0.78) or pooled analysis (global P = 0.18). In conclusion, despite the potential importance of inflammation in prostate carcinogenesis, results from our large study of five PTGS2 SNPs does not support a strong association between PTGS2 variants and prostate cancer risk in non-Hispanic white men.

    View details for DOI 10.1093/carcin/bgm253

    View details for Web of Science ID 000254008300014

    View details for PubMedID 17999989

  • Polymorphisms of genes in the lipid metabolism pathway and risk of biliary tract cancers and stones: A population-based case-control study in shanghai, china CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Andreotti, G., Chen, J., Gao, Y., Rashid, A., Chen, B. E., Rosenberg, P., Sakoda, L. C., Deng, J., Shen, M., Wang, B., Han, T., Zhang, B., Yeager, M., Welch, R., Chanock, S., Fraumeni, J. F., Hsing, A. W. 2008; 17 (3): 525-534

    Abstract

    Biliary tract cancers, encompassing the gallbladder, extrahepatic bile duct, and ampulla of Vater, are uncommon yet highly fatal malignancies. Gallstones, the primary risk factor for biliary cancers, are linked with hyperlipidemia. We examined the associations of 12 single nucleotide polymorphisms of five genes in the lipid metabolism pathway with the risks of biliary cancers and stones in a population-based case-control study in Shanghai, China. We included 235 gallbladder, 125 extrahepatic bile duct, and 46 ampulla of Vater cancer cases, 880 biliary stone cases, and 779 population controls. Subjects completed an in-person interview and gave blood. Genotyping was conducted by TaqMan assay using DNA from buffy coats. The effects of APOE IVS1+69 (rs440446) and APOB IVS6+360C>T (rs520354) markers were limited to men. Men carrying the G allele of APOE IVS1+69 had a 1.7-fold risk of stones [95% confidence interval (95% CI), 1.2-2.4], a 1.8-fold risk of gallbladder cancer (95% CI, 1.0-3.3), a 3.7-fold risk of bile duct cancer (95% CI, 2.0-7.0), and a 4-fold risk of ampullary cancer (95% CI, 1.4-12.4). Male carriers of the T allele of APOB IVS6+360C>T had a 2-fold risk of bile duct cancer (95% CI, 1.2-3.4). The APOB T-T haplotype (APOB IVS6+360C>T, EX4+56C>T) was associated with a 1.6-fold risk of bile duct cancer (95% CI, 1.1-2.3). Male and female carriers of the T allele of LDLR IVS9-30C>T (rs1003723) had a 1.5-fold risk of bile duct cancer. Our findings suggest that gene variants in the lipid metabolism pathway contribute to the risk of biliary tract stones and cancers, particularly of the bile duct.

    View details for DOI 10.1158/1055-9965.EPI-07-2704

    View details for Web of Science ID 000254373600010

    View details for PubMedID 18296645

    View details for PubMedCentralID PMC2897750

  • TNF polymorphisms and prostate cancer risk PROSTATE Danforth, K. N., Rodriguez, C., Hayes, R. B., Sakoda, L. C., Huang, W., Yu, K., Calle, E. E., Jacobs, E. J., Chen, B. E., Andriole, G. L., Figueroa, J. D., Yeager, M., Platz, E. A., Michaud, D. S., Chanock, S. J., Thun, M. J., Hsing, A. W. 2008; 68 (4): 400-407

    Abstract

    Inflammation has been hypothesized to increase prostate cancer risk. Tumor necrosis factor (TNF) is an important mediator of the inflammatory process, but the relationship between TNF variants and prostate cancer remains unclear.We examined associations between six TNF single nucleotide polymorphisms (SNPs) (rs1799964, rs1800630, rs1799724, rs1800629, rs361525, rs1800610) and prostate cancer risk among 2,321 cases and 2,560 controls from two nested case-control studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 2,561, 5 SNPs) and the Cancer Prevention Study II Nutrition Cohort (Nutrition Cohort, n = 2,320, 6 SNPs). Odds ratios and 95% confidence intervals were estimated for individual SNPs and haplotypes in each cohort separately and in pooled analyses.No TNF SNP was associated with prostate cancer risk in PLCO (P-trend > or = 0.16), while in the Nutrition Cohort, associations were significant for 2 highly correlated variants (rs1799724, 1800610, r2 = 0.95; P-trend = 0.04 and 0.02, respectively). In pooled analyses, no single SNP was associated with prostate cancer risk (P-trend > or = 0.08). After adjustment for multiple testing, no SNP was associated with prostate cancer risk in either cohort individually or in the pooled analysis (P-trend all > or = 0.10). Haplotypes based on 5 TNF SNPs did not vary by case/control status in PLCO, but showed marginal associations in the Nutrition Cohort (global P = 0.06) and the pooled analysis (global P = 0.05).Despite somewhat suggestive haplotype results, overall our study does not support an association between TNF variants and prostate cancer risk.

    View details for DOI 10.1002/pros.20694

    View details for Web of Science ID 000253882900006

    View details for PubMedID 18196539

  • Selected base excision repair gene polymorphisms and susceptibility to biliary tract cancer and biliary stones: a population-based case-control study in China CARCINOGENESIS Huang, W., Gao, Y., Rashid, A., Sakoda, L. C., Deng, J., Shen, M., Wang, B., Han, T., Zhang, B., Chen, B. E., Rosenberg, P. S., Chanock, S. J., Hsing, A. W. 2008; 29 (1): 100-105

    Abstract

    Base excision repair (BER) corrects DNA damage caused by oxidative stress and chronic inflammation, putative risk factors for cancer. To understand the relationship between genetic variation in BER genes and risk of biliary tract cancer and biliary stones, we examined non-synonymous polymorphisms in three key BER genes-x-ray repair cross-complementing group 1 (XRCC1) (R194W, rs1799782; R280H, rs25489 and R399Q, rs25487), apurinic/apyrimidinic endonuclease (APEX1) (D148E, rs3136820) and 8-oxoguanine DNA glycosylase (OGG1) (S326C, rs1052133), in a population-based study of 411 biliary tract cancer cases (237 gallbladder, 127 bile duct and 47 ampulla of Vater), 891 biliary (gallbladder or bile duct) stone cases and 786 population controls conducted in Shanghai, China. Compared with subjects carrying the XRCC1 194RR genotype, those with the WW genotype had a 1.9-fold risk of bile duct cancer [odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1-3.5, P(trend) = 0.03], and compared with subjects carrying the XRCC1 280RR genotype, those with the XRCC1 280H allele had a 50% reduced risk of bile duct cancer (OR = 0.5, 95% CI = 0.3-0.9, P(trend) = 0.05). The effect of the R280H polymorphism persisted (P(trend) = 0.03), when all three XRCC1 polymorphisms were jointly considered in the model, a finding supported by the haplotype results (covariate-adjusted global permutation P = 0.03). We also found an inverse association between the APEX1 148E allele and gallbladder stones (P(trend) = 0.03), but no association for the OGG1 polymorphism. This study suggests that genetic variants in XRCC1 and APEX1 may alter susceptibility to biliary tract cancer and stones. Further studies are required to confirm the reported associations.

    View details for DOI 10.1093/carcin/bgm247

    View details for Web of Science ID 000252904100014

    View details for PubMedID 17984110

  • MSR1 variants and the risks of prostate cancer and benign prostatic hyperplasia: a population-based study in China CARCINOGENESIS Hsing, A. W., Sakoda, L. C., Chen, J., Chokkalingam, A. P., Sesterhenn, I., Gao, Y., Xu, J., Zheng, S. L. 2007; 28 (12): 2530-2536

    Abstract

    Data from epidemiologic and twin studies suggest an important role of genetic susceptibility in prostate cancer. Variants of the macrophage scavenger receptor 1 (MSR1) gene have been linked to both hereditary and sporadic prostate cancer, although the evidence is inconclusive. Most studies have been conducted on Caucasians. The role of MSR1 in prostate cancer development among Asians, for whom rates of prostate cancer are low but rising rapidly, is unclear. To evaluate further the relationship between MSR1 variants and prostate cancer risk, we sequenced all the 11 MSR1 exons, exon-intron junctions, promoter regions, as well as 5' and 3' untranslated regions (UTRs) in 86 individuals from Shanghai, China. We identified a total of 21 sequence variants, including three novel variants that have not been reported previously. To balance genotyping cost and the capacity to capture sufficient genetic variation, we genotyped four haplotype-tagging variants (P275A, INDEL7, P346P and 3' UTR 70006), which capture 85% of the genetic variation in MSR1 in this population. These four variants, plus two other variants (PRO3 and INDEL1) that have been linked to prostate cancer risk in the previous studies, were typed for all study subjects, which included 130 prostate cancer cases, 130 patients with benign prostatic hyperplasia and 150 controls randomly selected from the population. Three of the six variants were associated with prostate cancer. Men with a P346P (a novel variant) G allele (AG + GG) had a significantly reduced risk of total prostate cancer [odds ratio = 0.47, 95% confidence interval (CI) 0.23-0.96], whereas those with a P275A G allele had a 37% reduced risk of prostate cancer (95% CI 0.39-1.02), with more pronounced reduction in risk seen for localized cancer cases (odds ratio = 0.25, 95% CI 0.12-0.52; P = 0.001). In addition, men with the INDEL7 variant had a 67% reduced risk of localized cancer (95% CI 0.16-0.68). Based on the four tagging variants, we inferred four major haplotypes that accounted for >90% of the haplotype variation in this population. The haplotype frequencies were significantly different between localized prostate cancer cases and controls, with a global P value of 0.004, and the haplotype containing the minor alleles of the P275A and INDEL7 variants was associated with a significantly reduced risk of localized prostate cancer (odds ratio = 0.28, 95% CI 0.13-0.59), relative to the most common haplotype. These results, although modest and confined mainly to localized prostate cancer, suggest that MSR1 polymorphisms may play a role in prostate cancer etiology in Chinese men. The role of MSR1 warrants further investigation in larger studies and other populations.

    View details for DOI 10.1093/carcin/bgm196

    View details for Web of Science ID 000251505800013

    View details for PubMedID 17768178

  • Prevalence of monoclonal Gammopathy of undetermined significance among men in Ghana MAYO CLINIC PROCEEDINGS Landgren, O., Katzmann, J. A., Hsing, A. W., Pfeiffer, R. M., Kyle, R. A., Yeboah, E. D., Biritwum, R. B., Tettey, Y., Adjei, A. A., Larson, D. R., Dispenzieri, A., Melton, L. J., Goldin, L. R., McMaster, M. L., Caporaso, N. E., Rajkumar, S. V. 2007; 82 (12): 1468-1473

    Abstract

    To determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), in Ghanaian men vs white men and to test for evidence to support an underlying race-related predisposition of the 2-fold higher prevalence of MGUS in African Americans vs whites.Between September 1, 2004, and September 30, 2006, 917 men (50-74 years) underwent in-person interviews and physical examinations. Serum samples from all participants were analyzed by electrophoresis performed on agarose gel; any serum sample with a discrete or localized band was subjected to immunofixation. Age-adjusted and standardized (to the 2000 world population) prevalence estimates of MGUS and 95% confidence intervals (CIs) were computed in the Ghanaian men and compared with MGUS prevalence in 7996 white men from Minnesota. Associations between selected characteristics and MGUS prevalence were assessed by the Fisher exact test and logistic regression models.Of the 917 study participants, 54 were found to have MGUS, yielding an age-adjusted prevalence of 5.84 (95% CI, 4.27-7.40) per 100 persons. No significant variation was found by age group, ethnicity, education status, or prior infectious diseases. The concentration of monoclonal immunoglobulin was undetectable in 41 (76%) of the 54 MGUS cases, less than 1 g/dL in 10 patients (19%), and 1 g/dL or more in only 3 patients (6%). Compared with white men, the age-adjusted prevalence of MGUS was 1.97-fold (95% CI, 1.94-2.00) higher in Ghanaian men.The prevalence of MGUS in Ghanaian men was twice that in white men, supporting the hypothesis that race-related genetic susceptibility could explain the higher rates of MGUS in black populations. An improved understanding of MGUS and MM pathophysiology would facilitate the development of strategies to prevent progression of MGUS to MM.

    View details for Web of Science ID 000251384300005

    View details for PubMedID 18053453

  • Gallstones and the risk of biliary tract cancer: a population-based study in China BRITISH JOURNAL OF CANCER Hsing, A. W., Gao, Y., Han, T., Rashid, A., Sakoda, L. C., Wang, B., Shen, M., Zhang, B., Niwa, S., Chen, J., Fraumeni, J. F. 2007; 97 (11): 1577-1582

    Abstract

    We conducted a population-based study of 627 patients with biliary tract cancers (368 of gallbladder, 191 bile duct, and 68 ampulla of Vater), 1037 with biliary stones, and 959 healthy controls randomly selected from the Shanghai population, all personally interviewed. Gallstone status was based on information from self-reports, imaging procedures, surgical notes, and medical records. Among controls, a transabdominal ultrasound was performed to detect asymptomatic gallstones. Gallstones removed from cancer cases and gallstone patients were classified by size, weight, colour, pattern, and content of cholesterol, bilirubin, and bile acids. Of the cancer patients, 69% had gallstones compared with 23% of the population controls. Compared with subjects without gallstones, odds ratios associated with gallstones were 23.8 (95% confidence interval (CI), 17.0-33.4), 8.0 (95% CI 5.6-11.4), and 4.2 (95% CI 2.5-7.0) for cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, respectively, persisting when restricted to those with gallstones at least 10 years prior to cancer. Biliary cancer risks were higher among subjects with both gallstones and self-reported cholecystitis, particularly for gallbladder cancer (OR=34.3, 95% CI 19.9-59.2). Subjects with bile duct cancer were more likely to have pigment stones, and with gallbladder cancer to have cholesterol stones (P<0.001). Gallstone weight in gallbladder cancer was significantly higher than in gallstone patients (4.9 vs 2.8 grams; P=0.001). We estimate that in Shanghai 80% (95% CI 75-84%), 59% (56-61%), and 41% (29-59%) of gallbladder, bile duct, and ampulla of Vater cancers, respectively, could be attributed to gallstones.

    View details for DOI 10.1038/sj.bjc.6604047

    View details for Web of Science ID 000251172700018

    View details for PubMedID 18000509

    View details for PubMedCentralID PMC2360257

  • Obesity, metabolic syndrome, and prostate cancer 8th Postgraduate Nutrition Symposium on Metabolic Syndrome and the Onset of Cancer Hsing, A. W., Sakoda, L. C., Chua, S. C. AMER SOC NUTRITION-ASN. 2007: 843S–857S
  • Family history of gallstones and the risk of biliary tract cancer and gallstones: A population-based study in Shanghai, China INTERNATIONAL JOURNAL OF CANCER Hsing, A. W., Bai, Y., Andreotti, G., Rashid, A., Deng, J., Chen, J., Goldstein, A. M., Han, T., Shen, M., Fraumeni, J. F., Gao, Y. 2007; 121 (4): 832-838

    Abstract

    Cancers of the biliary tract arise from the gallbladder, extrahepatic bile ducts and ampulla of Vater. Although relatively uncommon, the incidence of biliary tract cancer rose more than 100% in Shanghai, China between 1972 and 1994. Gallstones are the predominant risk factor for biliary tract cancers, with over 60% of the cancer cases having gallstones. A familial tendency to gallstones has been reported and may elevate the risk of gallbladder cancer further. As part of a large population-based case-control study of biliary tract cancers in Shanghai, China, we examined the association between a family history of gallstones and biliary tract cancers as well as biliary stones. A total of 627 biliary tract cancers (368 gallbladder, 191 bile duct, 68 ampulla of Vater), 1,037 biliary stone cases (774 gallbladder, 263 bile duct) and 959 healthy subjects randomly selected from the population were included in this study. Information on family history of gallstones among first-degree relatives (i.e., parents, siblings, offspring) was obtained through a self-reported history during in-person interviews. A family history of gallstones was associated with increased risks of biliary stones [odds ratio (OR) = 2.8, 95% confidence interval (CI) = 2.1-3.8], gallbladder cancer (OR = 2.1, 95% CI = 1.4-3.3) and bile duct cancer (OR = 1.5, 95% CI = 0.9-2.5), after adjustment for age, gender, marital status, education, smoking, alcohol drinking and body mass index. For gallbladder cancer, subjects with gallstones but without a family history of gallstones had a 21-fold risk (95% CI 14.8-30.1), while those with both gallstones and a positive family history had a 57-fold risk (95% CI 32.0-110.5). Significant risks for gallbladder cancer persisted after additional adjustment for gallstones, and when the analysis was restricted to subjects with first-degree relatives whose gallstones were treated with cholecystectomy. The significant associations with a family history of gallstones were seen for all first-degree relatives, including parents, siblings and offspring, but not spouses. This large population-based study not only supports the role of gallstones in biliary carcinogenesis but also suggests that the underlying genetic or lifestyle determinants of stones within families contribute to the risk of biliary tract cancer.

    View details for DOI 10.1002/ijc.22756

    View details for Web of Science ID 000248283300018

    View details for PubMedID 17450525

    View details for PubMedCentralID PMC2885776

  • Benign prostatic hyperplasia and subsequent risk of bladder cancer BRITISH JOURNAL OF CANCER Kang, D., Chokkalingam, A. P., Gridley, G., Nyren, O., Johansson, J. E., Adami, H. O., Silverman, D., Hsing, A. W. 2007; 96 (9): 1475-1479

    Abstract

    We evaluated the risk of bladder cancer in a cohort of 79,280 Swedish men hospitalised for benign prostatic hyperplasia (BPH), identified in the Swedish Inpatient Register between 1964 and 1983 and followed until 1989 via multiple record linkages with nationwide data on cancer registry, death and emigration. Standardised incidence ratios (SIRs), the ratios of the observed to the expected numbers of incident bladder cancers, were used to calculate the risk associated with BPH. The expected number was calculated by multiplying the number of person-years by the age-specific cancer incidence rates in Sweden for each 5-year age group and calendar year of observation. Analyses were stratified by BPH treatment, latency, calendar year and presence of genitourinary (GU) comorbid conditions. After excluding the first 3 years of follow-up after the index hospitalisation, we observed 506 incident bladder cancer cases during follow-up in the cohort. No overall increased risk of bladder cancer was apparent in our main analysis involving the entire BPH cohort. However, among BPH patients with transurethral resection of the prostate (TURP), there was an increased risk in all follow-up periods; SIRs of bladder cancer during years 4-6 of follow-up was 1.22 (95% confidence interval=1.02-1.46), 1.32 for 7-9 years of follow-up, and 1.47 for 10-26 years of follow-up. SIRs of bladder cancer among TURP-treated BPH patients were particularly elevated among those with comorbid conditions of the GU tract (e.g., stone, infection, etc.); 1.72, 1.74 and 2.01 for 4-6, 7-9, 10-26 years of follow-up, respectively, and also for those whose diagnoses occurred before 1975, when TURP was more likely to be performed by a urologist than a general practitioner: 1.87, 1.90 and 1.74, respectively. These findings suggest that BPH overall is not associated with bladder cancer risk. However, among men treated with TURP, particularly those with other comorbid GU tract conditions, risk of bladder cancer was elevated.

    View details for DOI 10.1038/sj.bjc.6603730

    View details for Web of Science ID 000246162600026

    View details for PubMedID 17473820

    View details for PubMedCentralID PMC2360186

  • Molecular epidemiology of prostate cancer: hormone-related genetic loci FRONTIERS IN BIOSCIENCE-LANDMARK Chokkalingam, A. P., Stanczyk, F. Z., Reichardt, J. K., Hsing, A. W. 2007; 12: 3436-3460

    Abstract

    Prostate cancer is the most common non-skin cancer and the second leading cause of cancer deaths among men in most Western countries. Despite its high morbidity and mortality, the etiology of prostate cancer remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data, including serological and genetic studies, are inconclusive. In this chapter, we review the status of serologic studies and discuss the importance of intra-prostatic hormone levels in possibly clarifying the often-contradictory data on serologic studies. To provide insights and directions for epidemiologic research on hormones and prostate cancer, this review centers on the molecular epidemiology of hormone-related genetic loci. These loci have been investigated in a number of studies to date and will undoubtedly expand even further as rich new genetic information sources and high-throughput genotyping and analysis methods become available. Due to the enormous number of these loci, we recommend careful analysis and cautious interpretation of studies of genetic markers, including microsatellites and single nucleotide polymorphisms (SNPs), as false positive and negative results are likely due to limited statistical power, multiple hypothesis testing, population stratification, or non-representative population sampling. This review also highlights the need for replication in various populations, as well as reasons for performing functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations. The time is ripe for concerted, large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies.

    View details for DOI 10.2741/2325

    View details for Web of Science ID 000246157900055

    View details for PubMedID 17485312

  • Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hsing, A. W., Stanczyk, F. Z., Belanger, A., Schroeder, P., Chang, L., Falk, R. T., Fears, T. R. 2007; 16 (5): 1004-1008

    Abstract

    There is an increasing trend to apply gas chromatography combined with mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS) assay methods to large-scale epidemiologic studies for the measurement of serum sex steroids. These methods are generally considered the gold standard for sex steroid measurements because of their accuracy, sensitivity, turnaround time, and ability to assess a more complete panel of steroid metabolites in the same run. In this report, we evaluated the precision, including within-batch (intra) and between-batch (inter) reproducibility, of steroid hormone measurements determined by GC-MS and LC-MS/MS assays and RIA and compared measurements among these methods. Specifically, 282 overnight fasting serum samples from 20 male volunteers were analyzed for 12 steroid metabolites by GC-MS or LC-MS/MS in one lab over a 4-month period. Six of the analytes were also measured by RIA in another lab. Unconjugated hormones, including testosterone, dihydrotestosterone, dehydroepiandrosterone, androstenedione, androst-5-ene-3beta,17beta-diol, estrone, and estradiol, were measured by GC-MS, whereas conjugated hormones, including DHEA sulfate, androsterone glucuronide, 5alpha-androstane-3alpha,17beta-diol 3-glucuronide, 5alpha-androstane-3alpha,17beta-diol 17-glucuronide, and estrone sulfate, were measured by LC-MS/MS. A subset of these hormones, including testosterone, dihydrotestosterone, androstenedione, 5alpha-androstane-3alpha,17beta-diol 17-glucuronide, estrone, and estradiol, were also measured by RIA following extraction and chromatography. We used the coefficient of variation (CV) and the intraclass correlation coefficient (ICC) to assess within- and between-batch assay variations. For the 12 analytes measured by GC-MS or LC-MS/MS, CVs and ICCs for within- and between-batch measurements were similar, with CVs ranging from 6.1% to 21.4% and ICCs ranging from 87.6% to 99.2%. The six analytes measured by RIA had good CVs and ICCs, with CVs <10% and ICCs >70% (range, 71.7-99.7%). For the six metabolites that were measured by both methods, the CVs were similar, whereas the ICCs were generally higher with the GC-MS method. The absolute values for each analyte measured by RIA and GC-MS differed, with RIAs usually yielding markedly higher levels than GC-MS, although the Pearson and Spearman correlation coefficients for these six analytes were near one and all were significant (P < 0.001). Our results show that RIA, GC-MS, and LC-MS/MS assays for androgens and estrogens in the two labs included in the study have good reproducibility, as measured by small CVs (<15%) and high ICCs (>80%), with the exception of estradiol (71.7%) when measured by RIA. Despite substantial differences in absolute measurements of sex steroid hormones by RIA and MS methods, correlations between the two assays for the six sex steroids measured in the two labs were high (>0.9). However, it is important for future large epidemiologic studies to incorporate MS with high reproducibility and specificity to measure a more complete profile of androgen and estrogen metabolites to clarify the role of sex steroids in prostate cancer.

    View details for DOI 10.1158/1055-9965.EPI-06-0792

    View details for Web of Science ID 000246649200026

    View details for PubMedID 17507629

  • Biliary tract cancer and stones in relation to chronic liver conditions: A population-based study in Shanghai, China INTERNATIONAL JOURNAL OF CANCER Hsing, A. W., Gao, Y., McGlynn, K. A., Niwa, S., Zhang, M., Han, T., Wang, B., Chen, J., Sakoda, L. C., Shen, M., Zhang, B., Deng, J., Rashid, A. 2007; 120 (9): 1981-1985

    Abstract

    Biliary tract cancers are relatively rare but fatal tumors. Apart from a close link with gallstones and cholangitis, risk factors for biliary tract cancer are obscure. Chronic liver conditions, including liver cirrhosis, have been linked to a higher risk of biliary tract cancer. In a population-based case-control study conducted in Shanghai, China, we investigated the relationships of a history of chronic hepatitis and liver cirrhosis as well as a family history of liver cancer with biliary tract cancer risk. The study included 627 patients with biliary tract cancers (368 gallbladder, 191 bile duct and 68 ampulla of Vater), 1,037 patients with biliary stones (774 gallbladder stones and 263 bile duct stones) and 959 healthy subjects randomly selected from the population. Bile duct cancer was associated with self-reports of chronic liver conditions, including a history of chronic hepatitis (OR = 2.0, 95% CI 0.9-4.4), liver cirrhosis (OR = 4.7, 95% CI 1.9-11.7) and a family history of primary liver cancer (OR = 2.0, 95% CI 1.0-3.9). The excess risk persisted after adjustment for gallstones and were more pronounced among subjects without gallstones (OR = 5.0, 95% CI 1.3-20.0 and OR = 4.9, 95% 2.0-12.2, respectively). History of liver conditions was also associated with an excess of biliary stones (OR = 1.9, 95% CI 1.2-3.0). No association was found for cancers of the gallbladder and ampulla of Vater. A history of chronic hepatitis and cirrhosis may be risk factors for extraheptic bile duct cancer. Given that chronic infection with hepatitis B virus (HBV) is the most common cause of liver disease in China, serologic markers of HBV need to be measured in future studies to examine the link between HBV and bile duct cancer.

    View details for DOI 10.1002/ijc.22375

    View details for Web of Science ID 000244972000021

    View details for PubMedID 17278101

  • A partially linear tree-based regression model for assessing complex joint gene-gene and gene-environment effects GENETIC EPIDEMIOLOGY Chen, J., Yu, K., Hsing, A., Therneau, T. M. 2007; 31 (3): 238-251

    Abstract

    The success of genetic dissection of complex diseases may greatly benefit from judicious exploration of joint gene effects, which, in turn, critically depends on the power of statistical tools. Standard regression models are convenient for assessing main effects and low-order gene-gene interactions but not for exploring complex higher-order interactions. Tree-based methodology is an attractive alternative for disentangling possible interactions, but it has difficulty in modeling additive main effects. This work proposes a new class of semiparametric regression models, termed partially linear tree-based regression (PLTR) models, which exhibit the advantages of both generalized linear regression and tree models. A PLTR model quantifies joint effects of genes and other risk factors by a combination of linear main effects and a non-parametric tree -structure. We propose an iterative algorithm to fit the PLTR model, and a unified resampling approach for identifying and testing the significance of the optimal "pruned" tree nested within the tree resultant from the fitting algorithm. Simulation studies showed that the resampling procedure maintained the correct type I error rate. We applied the PLTR model to assess the association between biliary stone risk and 53 single nucleotide polymorphisms (SNPs) in the inflammation pathway in a population-based case-control study. The analysis yielded an interesting parsimonious summary of the joint effect of all SNPs. The proposed model is also useful for exploring gene-environment interactions and has broad implications for applying the tree methodology to genetic epidemiology research.

    View details for DOI 10.1002/gepi.20205

    View details for Web of Science ID 000245128200006

    View details for PubMedID 17266115

  • Obesity, diabetes, and risk of prostate cancer: Results from the prostate cancer prevention trial CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gong, Z., Neuhouser, M. L., Goodman, P. J., Albanes, D., Chi, C., Hsing, A. W., Lippman, S. M., Platz, E. A., Pollak, M. N., Thompson, I. M., Kristal, A. R. 2006; 15 (10): 1977-1983

    Abstract

    Studies on the relationship between obesity and prostate cancer incidence are inconsistent. In part, this inconsistency may be due to a differential effect of obesity on low-grade and high-grade cancer or confounding of the association of obesity with prostate cancer risk by diabetes. We investigated the associations of obesity and diabetes with low-grade and high-grade prostate cancer risk. Data were from 10,258 participants (1,936 prostate cancers) in the Prostate Cancer Prevention Trial who all had cancer presence or absence determined by prostate biopsy. Multiple logistic regression was used to model the risk of total prostate cancer, and polytomous logistic regression was used to model the risk of low-grade and high-grade prostate cancer. Compared with men with body mass index < 25, obese men (body mass index > or =30) had an 18% [odds ratio (OR), 0.82; 95% confidence interval (95% CI), 0.69-0.98] decreased risk of low-grade prostate cancer (Gleason <7) and a 29% (OR, 1.29; 95% CI, 1.01-1.67) increased risk of high-grade prostate cancer (Gleason > or =7) or, alternatively, a 78% (OR, 1.78; 95% CI, 1.10-2.87) increased risk defining high-grade cancer as Gleason sum 8 to 10. Diabetes was associated with a 47% (OR, 0.53; 95% CI, 0.34-0.83) reduced risk of low-grade prostate cancer and a 28% (OR, 0.72; 95% CI, 0.55-0.94) reduced risk of high-grade prostate cancer. Associations of obesity or diabetes with cancer risk were not substantially changed by mutually statistical controlling for each other. Obesity increases the risk of high-grade but decreases the risk of low-grade prostate cancer, and this relationship is independent of the lower risk for prostate cancer among men with diabetes.

    View details for DOI 10.1158/1055-9965.EPI-06-0477

    View details for Web of Science ID 000241616800035

    View details for PubMedID 17035408

  • Rising prostate cancer rates in South Korea PROSTATE Park, S. K., Sakoda, L. C., Kang, D., Chokkalingam, A. P., Lee, E., Shin, H., Ahn, Y., Shin, M., Lee, C., Lee, D., Blair, A., Devesa, S. S., Hsing, A. W. 2006; 66 (12): 1285-1291

    Abstract

    Prostate cancer incidence and mortality rates in South Korea are relatively low, but rising steadily.We examined age-standardized incidence and mortality trends of prostate cancer in South Korea to gain further insight into prostate cancer etiology.Although prostate cancer incidence has been low (7.9 per 100,000 man-years), it has increased up to 28.2% between 1996-1998 and 1999-2001. Prostate cancer mortality increased 12.7-fold over a 20-year period. Despite the increase in prostate cancer incidence and mortality rates, marked differences in rates remain for Koreans, Korean Americans, and Caucasian Americans.The rising rates of prostate cancer in South Korea cannot be attributed entirely to PSA screening due to the low PSA screening prevalence; this trend is most likely related to increased westernization among Koreans. Interdisciplinary epidemiological studies incorporating the collection of biological samples are needed to clarify the extent to which lifestyle and genetic factors contribute to the observed racial disparity.

    View details for DOI 10.1002/pros.20419

    View details for Web of Science ID 000239739300007

    View details for PubMedID 16741923

  • Tea drinking and the risk of biliary tract cancers and biliary stones: A population-based case-control study in Shanghai, China INTERNATIONAL JOURNAL OF CANCER Zhang, X., Andreotti, G., Gao, Y., Deng, J., Liu, E., Rashid, A., Wu, K., Sun, L., Sakoda, L. C., Cheng, J., Shen, M., Wang, B., Han, T., Zhang, B., Gridley, G., Fraumeni, J. F., Hsing, A. W. 2006; 118 (12): 3089-3094

    Abstract

    Biliary tract cancers, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Apart from gallstones, etiologic factors for biliary tract cancer are not clearly defined. Several epidemiologic studies have suggested that consumption of tea, especially green tea, is protective against a variety of cancers, including gastrointestinal malignancies. As part of a large population-based case-control study of biliary tract disease in Shanghai, China, we evaluated the effects of tea consumption on the risk of biliary tract cancers and biliary stones. The study included 627 incident cases with biliary tract cancer, 1,037 cases with biliary stones and 959 randomly selected controls. Study subjects were interviewed to ascertain data on demographic, medical and dietary factors, including tea consumption. Forty-one percent of the controls were ever tea drinkers, defined as those who consumed at least 1 cup of tea per day for at least 6 months. After adjustment for age, education and body mass index, among women, ever tea drinkers had significantly reduced risks of biliary stones (OR = 0.73, 95% CI = 0.54-0.98) and gallbladder cancer (OR = 0.56, 95% CI = 0.38-0.83). The inverse relationship between tea consumption and gallbladder cancer risk was independent of gallstone disease. Among men, tea drinkers were more likely to be cigarette smokers, and the risk estimates were generally below 1.0, but were not statistically significant. Further studies are needed to confirm these results in other populations and clarify the hormonal and other mechanisms that may be involved.

    View details for DOI 10.1002/ijc.21748

    View details for Web of Science ID 000237331600023

    View details for PubMedID 16395699

    View details for PubMedCentralID PMC2885773

  • Prostate cancer epidemiology FRONTIERS IN BIOSCIENCE-LANDMARK Hsing, A. W., Chokkalingam, A. P. 2006; 11: 1388-1413

    Abstract

    Prostate cancer is the most common non-skin cancer among men in most western populations, and it is the second leading cause of cancer death among U.S. men. Despite its high morbidity, the etiology of prostate cancer remains largely unknown. Advancing age, race, and a family history of prostate cancer are the only established risk factors. Many putative risk factors, including androgens, diet, physical activity, sexual factors, inflammation, and obesity, have been implicated, but their roles in prostate cancer etiology remain unclear. It is estimated that as much as 42% of the risk of prostate cancer may be accounted for by genetic influences, including individual and combined effects of rare, highly penetrant genes, more common weakly penetrant genes, and genes acting in concert with each other. Numerous genetic variants in the androgen biosynthesis/metabolism, carcinogen metabolism, DNA repair, and chronic inflammation pathways, have been explored, but the results are largely inconclusive. The pathogenesis of prostate cancer likely involves interplay between environmental and genetic factors. To unravel these complex relationships, large well-designed interdisciplinary epidemiologic studies are needed. With newly available molecular tools, a new generation of large-scale multidisciplinary population-based studies is beginning to investigate gene-gene and gene-environment interactions. Results of these studies may lead to better detection, treatment, and, ultimately, prevention of prostate cancer.

    View details for Web of Science ID 000234180200019

    View details for PubMedID 16368524

  • Genetic polymorphisms of interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer CANCER RESEARCH Michaud, D. S., Daugherty, S. E., Berndt, S. I., Platz, E. A., Yeager, M., Crawford, E. D., Hsing, A., Huang, W. Y., Hayes, R. B. 2006; 66 (8): 4525-4530

    Abstract

    Chronic intraprostatic inflammation is suspected to play a role in the pathogenesis of prostate cancer. Polymorphisms in cytokine genes can influence inflammation and immune response and may be related to the risk of prostate cancer. Four common single nucleotide polymorphisms (SNPs) in the genes encoding interleukin-1B (IL-1B), IL-6, and IL-8 were assessed in 503 prostate cancer cases and 652 controls, and three SNPs in IL-10 were assessed in an additional 817 prostate cancer cases and 1,190 controls (for a total of 1,320 prostate cancer cases and 1,255 controls). Cases and controls were selected from the on-going Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial and were frequency matched on age, ethnicity, time-period since initial screening, and date of blood draw. Single-locus analyses were conducted using conditional logistic regression. In addition, we did a haplotype analysis for the three IL-10 SNPs tested. Overall, no associations were detected between the seven polymorphisms in the four cytokine genes examined in this study and prostate cancer risk. Further stratifying by use of nonsteroidal anti-inflammatory drugs did not modify the associations. Findings were similar for early or advanced prostate cancers. Similarly, we observed no association between the major IL-10 haplotypes and the risk of prostate cancer. At least seven common polymorphisms in genes of inflammatory cytokines IL-1B, IL-6, IL-8, and IL-10 do not seem to play a role in the risk of prostate cancer.

    View details for DOI 10.1158/008-5472.CAN-05-3987

    View details for Web of Science ID 000236843200072

    View details for PubMedID 16618781

  • Genetic variants of DNA repair genes and prostate cancer: A population-based study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ritchey, J. D., Huang, W. Y., Chokkalingam, A. P., Gao, Y. T., Deng, J., Levine, P., Stanczyk, F. Z., Hsing, A. W. 2005; 14 (7): 1703-1709

    Abstract

    As part of a population-based case-control study in Shanghai, China, we investigated whether variants in several DNA repair genes, either alone or in conjunction with other risk factors, are associated with prostate cancer risk. Genomic DNA from 162 patients newly diagnosed with prostate cancer and 251 healthy men randomly selected from the population were typed for five nonsynonymous DNA repair markers. We found that the XRCC1-Arg399Gln AA and the MGMT-Leu84Phe CT+TT genotypes were associated with an increased risk of prostate cancer [odds ratio (OR), 2.18; 95% confidence interval (CI), 0.99-4.81 and OR, 1.99; 95% CI, 1.19-3.34, respectively]. In contrast, XRCC3-Thr241Met, XPD-Lys751Gln, and MGMT-Ile143Val markers showed no significant associations with risk, although due to the much lower frequency of their variant alleles in this population we cannot rule out small to modest effects. There was a significant interaction between the MGMT-84 marker and insulin resistance (P(interaction) = 0.046). Relative to men with the MGMT-84 CC genotype and a low insulin resistance (<0.097), those having the CT-TT genotype and a greater insulin resistance had a 5.4-fold risk (OR, 5.39; 95% CI, 2.46-11.82). In addition, for the XRCC3-241 marker, relative to men with the CC genotype and a low intake of preserved foods (<12.7 g/d), those harboring the CT+TT genotype and having a higher intake of preserved foods (>12.7 g/d), which contain nitrosamines and nitrosamine precursors, had a significantly increased risk of prostate cancer risk (OR, 2.62; 95% CI, 1.13-6.06). In contrast, men with the CT+TT genotype and a low intake of preserved foods had a 69% reduction in risk (OR, 0.31; 95% CI, 0.10-0.96; P(interaction) = 0.005). These results suggest that genetic variants in the DNA repair pathways may be involved in prostate cancer etiology and that other risk factors, including preserved foods and insulin resistance, may modulate prostate cancer risk in combination with genetic susceptibility in these repair pathways. Replication in larger studies is necessary to preclude chance findings, particularly those among subgroups, and clarify the mechanisms involved.

    View details for Web of Science ID 000230525700019

    View details for PubMedID 16030105

  • Aspirin use and risk of biliary tract cancer: A population-based study in Shanghai, China CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Liu, E. J., Sakoda, L. C., Gao, Y. T., Rashid, A., Shen, M. C., Wang, B. S., Deng, J., Han, T. Q., Zhang, B. H., Fraumeni, J. F., Hsing, A. W. 2005; 14 (5): 1315-1318

    Abstract

    The association of gallbladder and bile duct cancers with gallstones, cholecystitis, and cholangitis suggest that chronic inflammation contributes to the carcinogenic process. However, the effect of nonsteroidal anti-inflammatory drugs, such as aspirin, on biliary tract cancer has not been well studied. In a population-based case-control study conducted in Shanghai, China, we examined the relationship between aspirin use and the risk of biliary disease. A total of 627 patients with biliary tract cancer, including cancers of the gallbladder (n = 368), extrahepatic bile duct (n = 191), and ampulla of Vater (n = 68); 1,037 patients with biliary stones; and 958 healthy adults were included in the study. Self-reported data on aspirin use was collected from study participants by in-person interview. The prevalence of aspirin use was low, with 5.7% of the population controls being regular users. After controlling for age, sex, education, and biliary stone status, aspirin use was associated with a reduced risk of gallbladder cancer [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.17-0.88]. An inverse relationship was also observed for frequency and duration of use and with younger age when starting use. In addition, there was a nonsignificant reduction in the risk of bile duct (OR, 0.48; 95% CI, 0.19-1.19) and ampullary cancers (OR, 0.22; 95% CI, 0.03-1.65) associated with aspirin use, whereas no clear association was seen with biliary stones (OR, 0.92; 95% CI, 0.59-1.44). Further studies of biliary tract cancer in other populations are needed to confirm these results and to elucidate the mechanisms that underlie the reduced risk associated with use of aspirin and possibly other nonsteroidal anti-inflammatory drugs.

    View details for Web of Science ID 000229032000045

    View details for PubMedID 15894693

  • Risk of prostate cancer and family history of cancer: a population based study in China PROSTATE CANCER AND PROSTATIC DISEASES Bai, Y., Gao, Y. T., Deng, J., Sesterhenn, I. A., Fraumeni, J. F., Hsing, A. W. 2005; 8 (1): 60-65

    Abstract

    We evaluated prostate cancer risk and family history of cancers using data from a case-control study in China. Cancer information among first-degree relatives was collected from 709 subjects (238 cases and 471 controls). None of the subjects reported a family history of prostate cancer. However, excess prostate cancer risk was associated with a family history of any cancer (OR = 1.79, 95% CI: 1.21-2.63) and esophageal cancer (OR = 2.39, 95% CI: 1.15-5.00). Nonsignificant risk was seen for family history of cancers of the stomach, lung, and female breast. Our results did not confirm the familial tendency toward prostate cancer but other cancers prevalent in China appeared to be aggregate, particularly esophageal cancer. Larger studies are needed to confirm these findings, and to clarify the genetic and lifestyle factors that may be involved.

    View details for DOI 10.1038/sj.pcan.4500775

    View details for Web of Science ID 000228553700022

    View details for PubMedID 15643451

  • Alterations of p16 and prognosis in biliary tract cancers from a population-based study in China CLINICAL CANCER RESEARCH Ueki, T., Hsing, A. W., Gao, Y. T., Wang, B. S., Shen, M. C., Cheng, J. R., Deng, J., Fraumeni, J. F., Rashid, A. 2004; 10 (5): 1717-1725

    Abstract

    Biliary tract cancer is an uncommon malignancy with a poor survival rate. We evaluated p16 gene alteration as a prognostic marker for this disease.We studied p16 gene alterations by sequencing, methylation, and loss of heterozygosity of chromosome 9p in 118 biliary tract carcinomas, including 68 gallbladder cancers, 33 extrahepatic bile duct cancers, and 17 ampullary cancers. Survival was evaluated in 57 patients with gallbladder carcinomas, 27 with bile duct carcinomas, and 16 with ampullary carcinomas with and without somatic p16 alterations detected by two different methods.p16 gene alterations including silent mutations were present in 61.8% gallbladder cancers, 54.5% bile duct cancers, and 70.6% ampullary cancers. p16 gene nonsilent mutations, p16 methylation, and loss of chromosome 9p21-22 that targets p14, p15, and p16 genes were present in 13 of 53 (24.5%), 8 of 54 (14.8%), and 32 of 44 (72.7%) gallbladder tumors; 5 of 25 (20.0%), 5 of 31 (16.1%), and 12 of 21 (57.1%) bile duct tumors; and 3 of 13 (23.1%), 6 of 15 (40.0%), and 8 of 16 (50.0%) ampullary tumors, respectively. The mean survival of patients with gallbladder cancers without p16 alterations was 21.5 +/- 14.8 months compared with 12.1 +/- 11.4 months for patients with p16 alterations (P = 0.02).Alteration of p16 gene alone or in combination with alterations of other tumor suppressor genes on chromosome 9p is a prognostic indicator in gallbladder carcinoma, with more favorable survival rates associated with carcinomas lacking p16 gene alterations.

    View details for Web of Science ID 000220089100023

    View details for PubMedID 15014024

  • Soy and isoflavone consumption in relation to prostate cancer risk in China CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lee, M. M., Gomez, S. L., Chang, J. S., Wey, M., Wang, R. T., Hsing, A. W. 2003; 12 (7): 665-668

    Abstract

    This case-control study in China evaluated the effect of soy food consumption and isoflavones (genistein and daidzein) on the risk of prostate cancer. One hundred and thirty-three cases and 265 age- and residential community-matched controls between the ages of 50 and 89 years were interviewed in person between 1989 and 1992. Usual consumption of soy foods and isoflavones was assessed using a food frequency questionnaire developed in China and a nutrient database developed and validated in Asian-American populations. The age- and total calorie-adjusted odds ratio (OR) of prostate cancer risk comparing the highest tertile of tofu intake to the lowest tertile was 0.58 [95% confidence interval (CI), 0.35-0.96]. There were also statistically significant associations comparing the highest quartile of intake of soy foods (OR, 0.51; 95% CI, 0.28-0.95) and genistein (OR, 0.53; 95% CI, 0.29-0.97) with the lowest quartiles. There was also an indication of a reduced risk associated with intake of daidzein (OR, 0.56; 95% CI, 0.31-1.04 for the highest versus lowest quartile). Our results indicate a reduced risk of prostate cancer associated with consumption of soy foods and isoflavones. These findings should be confirmed in longitudinal follow-up studies in populations with varying risk of prostate cancer.

    View details for Web of Science ID 000184311700014

    View details for PubMedID 12869409

  • Insulin resistance and prostate cancer risk JOURNAL OF THE NATIONAL CANCER INSTITUTE Hsing, A. W., Gao, Y. T., Chua, S., Deng, J., Stanczyk, F. Z. 2003; 95 (1): 67-71

    Abstract

    Because high waist-to-hip ratio (WHR) and high serum insulin levels have been reported to be associated with an increased risk of prostate cancer, we assessed the relationship between insulin resistance and prostate cancer risk in Chinese men. We measured fasting serum glucose and insulin levels in 128 case and 306 control subjects and used the homeostasis model assessment to derive indices of insulin sensitivity and resistance. Relative to men in the lowest tertiles, men in the highest tertile of insulin sensitivity had a reduced risk of prostate cancer (odds ratio [OR] = 0.35, 95% confidence interval [CI] = 0.21 to 0.60), but men in the highest tertile of insulin resistance had an increased risk of prostate cancer (OR = 2.78, 95% CI = 1.63 to 4.72). Considering insulin resistance and WHR together, the effect of insulin resistance was apparent in all tertiles of WHR, with men in the highest tertile of insulin resistance and WHR having the highest risk (OR = 8.21, 95% CI = 2.84 to 23.70). The associations between prostate cancer risk and insulin sensitivity or resistance were independent of total caloric intake and serum levels of insulin-like growth factors, sex hormones, and sex hormone-binding globulin. Because of the retrospective design of this study, the role of insulin resistance in prostate cancer needs to be confirmed in prospective studies.

    View details for Web of Science ID 000180079200013

    View details for PubMedID 12509402

  • Allium vegetables and risk of prostate cancer: A population-based study JOURNAL OF THE NATIONAL CANCER INSTITUTE Hsing, A. W., Chokkalingam, A. P., Gao, Y. T., Madigan, M., Deng, J., Gridley, G., Fraumeni, J. F. 2002; 94 (21): 1648-1651

    Abstract

    Epidemiologic and laboratory studies suggest that allium vegetables and garlic constituents have antitumor effects. In a population-based, case-control study conducted in Shanghai, China, we investigated the association between intake of allium vegetables, including garlic, scallions, onions, chives, and leeks, and the risk of prostate cancer. We administered in-person interviews and collected information on 122 food items from 238 case subjects with incident, histologically confirmed prostate cancer and from 471 male population control subjects. Men in the highest of three intake categories of total allium vegetables (>10.0 g/day) had a statistically significantly lower risk (odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.76; P(trend)<.001) of prostate cancer than those in the lowest category (<2.2 g/day). Similar comparisons between categories showed reductions in risk for men in the highest intake categories for garlic (OR = 0.47, 95% CI = 0.31 to 0.71; P(trend)<.001) and scallions (OR = 0.30, 95% CI = 0.18 to 0.51; P(trend)<.001). The reduced risk of prostate cancer associated with allium vegetables was independent of body size, intake of other foods, and total calorie intake and was more pronounced for men with localized than with advanced prostate cancer.

    View details for Web of Science ID 000179045100013

    View details for PubMedID 12419792

  • K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: A population-based study in China CLINICAL CANCER RESEARCH Rashid, A., Ueki, T., Gao, Y. T., Houlihan, P. S., Wallace, C., Wang, B. S., Shen, M. C., Deng, J., Hsing, A. W. 2002; 8 (10): 3156-3163

    Abstract

    The genetic alterations in biliary tract cancer and clinicopathological associations have not been studied in large population-based studies.We evaluated genetic alterations such as K-ras mutation, p53 overexpression, microsatellite instability (MSI), and alterations of the polyadenine tract present in the transforming growth factor beta receptor type II (TGFbetaRII) gene in 126 biliary tract cancers: 75 gallbladder cancers, 33 bile duct cancers, and 18 ampullary cancers. These genetic alterations were compared with patient demographics and clinicopathological characteristics of the tumors.Mutation of the K-ras gene was present in 18 of 126 (14.3%) biliary tract cancers. K-ras mutation was present in 11 of 18 (61.1%) ampullary cancers, 5 of 33 (15.2%) bile duct cancers, and 2 of 75 (2.7%) gallbladder cancers (P = 0.000001). The mean survival of patients who had bile duct carcinomas with K-ras mutation was 3.0 +/- 2.2 months compared with 15.5 +/- 12.5 months for those without mutation (P = 0.03) but was not different for other tumor sites. p53 overexpression was present in 34 of 123 (27.6%) cancers. MSI-high (allelic shifts in 40% or more loci or alteration of the TGFbetaRII gene) was present in 4 of 126 (3.2%) biliary tract cancers without hereditary nonpolyposis colorectal cancer. MSI-high was more common in mucinous adenocarcinomas (P = 0.006) and in patients with early age of onset of cancer (P = 0.04).The genetic alterations in biliary tract cancers are dependent on the tumor subsite, histology, and age of onset and are associated with prognosis.

    View details for Web of Science ID 000178544900016

    View details for PubMedID 12374683

  • Body size and serum levels of insulin and leptin in relation to the risk of benign prostatic hyperplasia JOURNAL OF UROLOGY Dahle, S. E., Chokkalingam, A. P., Gao, Y. T., Deng, J., Stanczyk, F. Z., Hsing, A. W. 2002; 168 (2): 599-604

    Abstract

    Obesity has been implicated in the etiology of benign and malignant prostatic growth due to its influence on metabolic and endocrine changes. Because obesity is an important determinant of serum levels of insulin and leptin (the product of the obesity gene Ob), we investigated the role of obesity and serum levels of insulin and leptin in benign prostatic hyperplasia (BPH) etiology.Fasting serum levels of insulin and leptin as well as the body mass index, a measure of overall obesity, and waist-to-hip ratio, an indicator of abdominal obesity, were determined in 200 men newly diagnosed with BPH who were hospitalized for surgery and in 302 randomly selected healthy male subjects from the population in Shanghai, China.A higher waist-to-hip ratio and higher serum insulin were significantly associated with an increased risk of BPH. Relative to men in the lowest waist-to-hip ratio quartile (less than 0.856) those in the highest quartile (greater than 0.923) were at 2.4-fold risk (odds ratio 2.42, 95% confidence interval [CI] 1.34 to 4.37, test for trend p = 0.01). Similarly relative to men in the lowest quartile of insulin (less than 5.87 microU. per ml.) those in the highest quartile (greater than 9.76 microU. per ml.) were at significantly increased risk (odds ratio 2.47, 95% CI 1.35 to 4.54, test for trend p = 0.009). The effect of insulin on BPH risk was more pronounced in men in low and middle tertiles of the waist-to-hip ratio (odds ratios comparing high to low insulin tertiles 2.8 and 2.7, respectively), while among men in the highest waist-to-hip ratio tertile insulin was not significantly associated with BPH risk. In contrast, we found no significant odds ratio comparing the highest to lowest quartiles of leptin (odds ratio 0.62, 95% CI 0.33 to 1.17) or body mass index (odds ratio 1.64, 95% CI 0.96 to 2.81).Our results suggest that abdominal obesity and increasing serum insulin, and possibly overall obesity but not serum leptin are associated with a higher risk of BPH. Further prospective and laboratory studies are needed to confirm these results and elucidate the underlying mechanisms.

    View details for Web of Science ID 000176813300044

    View details for PubMedID 12131317

  • Insulin-like growth factors and risk of benign prostatic hyperplasia PROSTATE Chokkalingam, A. P., Gao, Y. T., Deng, J., Stanczyk, F. Z., Sesterhenn, I. A., Mostofi, F. K., Fraumeni, J. F., Hsing, A. W. 2002; 52 (2): 98-105

    Abstract

    Insulin-like growth factors (IGFs) have potent growth mitogenic and anti-apoptotic effects on prostate tissue, whereas IGF binding proteins (IGFBPs) inhibit growth of prostatic tissue. The IGF axis has been implicated in prostate cancer risk, but its role in benign prostatic hyperplasia (BPH) is unclear.Plasma levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were determined from the fasting bloods of 206 BPH cases admitted for treatment and 306 randomly selected population controls in Shanghai, China.Relative to the lowest tertile, men in the highest tertile of IGF-I levels had a significantly elevated risk of BPH (odds ratio [OR] = 2.80, 95% confidence interval [95% CI] = 1.60-4.92; P(trend) < 0.001). Results for IGF-I were more pronounced after adjustment for serum androgens. In contrast, men in the highest IGFBP-3 tertile had a significantly reduced risk (OR = 0.40; 95% CI = 0.23-0.69; P(trend) < 0.001). No associations of BPH with IGF-II and IGFBP-1 were observed.As has been previously observed for prostate cancer, we found that IGF-I and IGFBP-3 are associated with BPH risk in China. Further investigation is needed to elucidate the role of the IGF axis in BPH etiology.

    View details for DOI 10.1002/pros.10096

    View details for Web of Science ID 000176431000002

    View details for PubMedID 12111701

  • Cigarette and alcohol consumption and the risk of colorectal cancer in Shanghai, China EUROPEAN JOURNAL OF CANCER PREVENTION Ji, B. T., Dai, Q., Gao, Y. T., Hsing, A. W., McLaughlin, J. K., Fraumeni, J. F., Chow, W. H. 2002; 11 (3): 237-244

    Abstract

    The relation of cigarette smoking and alcohol drinking to colorectal cancer risk has been inconsistent in the epidemiological literature. In a population-based case-control study of colorectal cancer in Shanghai, China, where the incidence rates are rising sharply, we examined the association with tobacco and alcohol use. Cases were aged 30-74 years and newly diagnosed with cancers of the colon (N = 931) or rectum (N = 874) between 1990 and 1992. Controls (N = 1552) were randomly selected among Shanghai residents, frequency-matched to cases by gender and age. Information on lifetime consumption of tobacco and alcohol, as well as demographic and other risk factors, was obtained through in-person interviews. Associations with cigarette smoking and alcohol use were estimated by odds ratios (ORs) and 95% confidence intervals (CIs). Among women, the prevalence of smoking and alcohol drinking was low, and no significant association with colon or rectal cancer was observed. Although cigarette smoking among men was not related overall to colon or rectal cancer risk, there was a 50% excess risk of rectal cancer (OR 1.5, 95% CI 0.9-2.5) among those who smoked 55 or more pack-years. Among men, former alcohol drinkers had an increased risk of colon cancer (OR 2.3, 95% CI 1.4-3.7) but not rectal cancer, while current drinkers had a 30-50% excess risk of colon cancer only among those with long-term (30+ years) and heavy (>560 g ethanol/week) consumption. The excess risks were mainly associated with hard liquor consumption, with no material difference in risk between proximal and distal colon cancer. Although cigarette smoking and alcohol drinking in general were not risk factors for colorectal cancers in Shanghai, there were small excess risks for rectal cancer among heavy smokers and colon cancer among heavy drinkers.

    View details for Web of Science ID 000177127800007

    View details for PubMedID 12131657

  • Polymorphic CAG/CAA repeat length in the AIB1/SRC-3 gene and prostate cancer risk: A population-based case-control study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hsing, A. W., Chokkalingam, A. P., Gao, Y. T., Wu, G., Wang, X., Deng, J., Cheng, J. R., Sesterhenn, I. A., Mostofi, F. K., Chiang, T. Y., Chen, Y. L., Stanczyk, F. Z., Chang, C. S. 2002; 11 (4): 337-341

    Abstract

    In an earlier report, we showed that a shorter CAG repeat length in the androgen receptor (AR) gene is associated with an increased risk of prostate cancer in China, the population with the lowest reported prostate cancer incidence in the world. Because AR coactivators enhance transactivation of AR, in this report we evaluated the relationship of a CAG/CAA repeat length polymorphism in the AIB1/SRC-3 gene (amplified in breast cancer gene 1, a steroid receptor coactivator and an AR coactivator) with prostate cancer risk in a population-based case-control study in China. Genomic DNA from 189 prostate cancer patients and 301 healthy controls was used for the PCR-based assay. The AIB1/SRC-3 CAG/CAA repeat length ranged from 24 to 32, with the most common repeat length being 29. Homozygous 29/29 and heterozygous 28/29 were the most common genotypes, with 44 and 30% of the controls harboring these genotypes, respectively. Relative to subjects homozygous for 29 CAG/CAA repeats (29/29 genotype), individuals with the <29/29 genotype had a nonsignificant 31% increased risk [odds ratio (OR), 1.31; 95% confidence interval (CI), 0.87-1.97], whereas those homozygous for the <29 allele had a significant 81% excess risk (OR, 1.81; 95% CI, 1.00-3.28). The combined effect of CAG repeat lengths in the AR and AIB1/SRC-3 genes was also evaluated. Relative to men with both the 29/29 genotype of the AIB1/SRC-3 gene and a long CAG repeat length (> or =23) in the AR gene, those with both the <29/<29 AIB1/SRC-3 genotype and a short CAG repeat length in the AR gene (<23) had a 2.8-fold risk (OR, 2.78; 95% CI, 1.24-6.26). Together, our data indicate that the CAG/CAA repeat length in the AIB1/SRC-3 gene may be associated with prostate cancer risk in Chinese men and that the combination of CAG/CAA repeat lengths in both the AIB1/SRC-3 and AR genes may provide a useful marker for clinically significant prostate cancer. Expanded studies in other populations are needed to confirm this association and the combined effect of AIB1/SRC-3 and other hormone-related genes in prostate cancer etiology.

    View details for Web of Science ID 000174908000002

    View details for PubMedID 11927493

  • International trends and patterns of primary liver cancer INTERNATIONAL JOURNAL OF CANCER McGlynn, K. A., Tsao, L., Hsing, A. W., Devesa, S. S., Fraumeni, J. F. 2001; 94 (2): 290-296

    Abstract

    Primary liver cancer (PLC) is common in many areas of the developing world, but uncommon in most of the developed world. Some evidence suggests, however, that the global pattern of PLC may be changing. To clarify this issue, we examined incidence rates for PLC over the 15-year time period, 1978-92, in selected cancer registries around the world. With some exceptions, developed countries have experienced PLC increases in incidence whereas developing countries have experienced declines. Although the reasons for the trends are not entirely clear, the increased seroprevalence of HCV in the developed world and the elimination of HBV-cofactors in the developing world are likely to have contributed to the patterns. Further progress against PLC may be seen in the developing world once the HBV-vaccinated segment of the population reaches adulthood. Published 2001 Wiley-Liss, Inc.

    View details for Web of Science ID 000171045900021

    View details for PubMedID 11668511

  • Polymorphic markers in the SRD5A2 gene and prostate cancer risk: A population-based case-control study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hsing, A. W., Chen, C., Chokkalingam, A. P., Gao, Y. T., Dightman, D. A., Nguyen, H. T., Deng, J., Cheng, J. R., Sesterhenn, I. A., Mostofi, F. K., Stanczyk, F. Z., Reichardt, J. K. 2001; 10 (10): 1077-1082

    Abstract

    It has been suggested that the activity of the steroid 5alpha-reductase type II enzyme (encoded by the SRD5A2 gene) may be associated with prostate cancer risk and that population differences in this enzyme's activity may account for part of the substantial racial/ethnic disparity in prostate cancer risk. To provide etiological clues, we evaluated the relationships of four polymorphic markers in the SRD5A2 gene, specifically, A49T (a substitution of threonine for alanine at codon 49), V89L (a substitution of leucine for valine at codon 89), R227Q (a substitution of glutamine for arginine at codon 227), and a (TA)n dinucleotide repeat, with prostate cancer risk in a population-based case-control study in China, a population with the lowest reported prostate cancer incidence rate in the world. Genotypes of these four markers were determined from genomic DNA of 191 incident cases of prostate cancer and 304 healthy controls using PCR-based assays, and serum androgen levels were measured in relation to these genotypes. All study subjects had the wild-type AA genotype of the A49T marker, and 99% had the RR genotype of the R227Q marker. For the V89L marker, prevalences of the LL, VV, and VL genotypes among controls were 35%, 21%, and 45%, respectively. Compared with men with the VV genotype, those with the LL genotype had a statistically nonsignificant 12% reduced risk (odds ratio = 0.88, 95% confidence interval, 0.53-1.47). In addition, men with the LL genotype had significantly higher serum levels of testosterone and significantly lower serum levels of 5alpha-androstane-3alpha,17beta-diol glucuronide than men with other genotypes. Men heterozygous for the (TA)0 allele of the (TA)n marker had a modest, statistically nonsignificant risk reduction (odds ratio = 0.67; 95% confidence interval, 0.39-1.12) compared with men homozygous for the (TA)0 allele, along with significantly higher serum dihydrotestosterone levels. The observed V89L genotype prevalences and the association between V89L genotypes and serum androgen levels support the hypothesis that genotypes associated with lower levels of 5alpha-reductase activity are more common in low-risk populations. Although we found no statistically significant associations of these SRD5A2 polymorphisms with prostate cancer risk, a small effect of these markers cannot be ruled out because of the rarity of certain marker genotypes. Larger studies are needed to further clarify the role of these markers and to elucidate whether genetic diversity of the SRD5A2 gene, alone or in combination with other susceptibility genes, can help explain the large racial/ethnic differences in prostate cancer risk.

    View details for Web of Science ID 000171492900009

    View details for PubMedID 11588134

  • Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: A population-based case-control study in China CANCER RESEARCH Chokkalingam, A. P., McGlynn, K. A., Gao, Y. T., Pollak, M., Deng, J., Sesterhenn, I. A., Mostofi, F. K., Fraumeni, J. F., Hsing, A. W. 2001; 61 (11): 4333-4336

    Abstract

    Operating through the vitamin D receptor (VDR), vitamin D inhibits prostate cancer growth and increases insulin-like growth factor binding protein (IGFBP) expression, suggesting that the vitamin D and insulin-like growth factor (IGF) regulatory systems may operate together to affect prostate cancer. Among 191 newly diagnosed prostate cancer cases and 304 randomly selected population controls in Shanghai, China, we found no significant association between the BsmI or FokI VDR gene polymorphisms and prostate cancer risk. However, we found that among men with the ff FokI genotype, those in the highest tertile of plasma IGFBP-3 had a decreased risk versus those in the lowest tertile (odds ratio, 0.14; 95% confidence interval, 0.04-0.56; P(trend) < 0.01), whereas among men with the FF and Ff genotypes, IGFBP-3 was not associated with risk. Similarly, IGFBP-1 was inversely associated with prostate cancer risk only among men with the ff FokI genotype (odds ratio, 0.25; 95% confidence interval, 0.07-0.85; P(trend) = 0.02). No such FokI genotype-specific effects were observed for IGF-I or IGF-II. Our findings in a low-risk population suggest that the IGF and vitamin D regulatory systems may interact to affect prostate cancer risk. Larger studies are needed to confirm these findings and clarify the underlying mechanisms.

    View details for Web of Science ID 000169051100009

    View details for PubMedID 11389055

  • Insulin-like growth factors and prostate cancer: A population-based case-control study in China CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chokkalingam, A. P., Pollak, M., Fillmore, C. M., Gao, Y. T., Stanczyk, F. Z., Deng, J., Sesterhenn, I. A., Mostofi, F. K., Fears, T. R., Madigan, M. P., Ziegler, R. G., Fraumeni, J. F., Hsing, A. W. 2001; 10 (5): 421-427

    Abstract

    Insulin-like growth factors (IGFs) have potent mitogenic and antiapoptotic effects on prostate epithelial cells. Through modulation of IGF bioactivity and other mechanisms, IGF-binding proteins (IGFBPs) also have growth-regulatory effects on prostate cells. Recently, IGF-I and IGFBP-3 have been implicated in prostate cancer risk among Western populations. To assess whether IGF-I, IGF-II, IGFBP-1, or IGFBP-3 are also associated with prostate cancer in a low-risk population, we measured plasma levels of these factors among 128 newly diagnosed prostate cancer cases and 306 randomly selected population controls in Shanghai, China. Relative to the lowest quartile of IGF-I levels, men in the highest quartile had a 2.6-fold higher prostate cancer risk, with a significant trend [odds ratio (OR) = 2.63; 95% confidence interval (95% CI) = 1.19-5.79; P(trend) = 0.01]. In contrast, men in the highest quartile of IGFBP-3 levels had a 46% decreased risk relative to the lowest quartile (OR = 0.54; 95% CI = 0.26-1.15; P(trend) = 0.08). A similar but less distinct result was observed for IGFBP-1 (OR = 0.60; 95% CI = 0.31-1.17; P(trend) = 0.25). Men in the highest quartile for the IGF-I:IGFBP-3 molar ratio (an indirect measure of free IGF-I) had a 2.5-fold higher risk compared with the lowest quartile (OR = 2.51; 95% CI = 1.32-4.75, P(trend) < 0.001). These associations were more pronounced after adjustment for serum 5alpha-androstane-3alpha,17beta-diol glucuronide and sex hormone-binding globulin levels. There was no significant association with IGF-II levels. Our findings in a low-risk population provide evidence that IGF-I, IGFBP-3, and IGFBP-1 are determinants of prostate cancer and indicate that additional studies are needed to evaluate their effects on ethnic and geographic incidence differentials and to elucidate carcinogenic mechanisms.

    View details for Web of Science ID 000168737800001

    View details for PubMedID 11352850

  • Body size and prostate cancer: A population-based case-control study in China CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hsing, A. W., Deng, J., Sesterhenn, I. A., Mostofi, F. K., Stanczyk, F. Z., Benichou, J., Xie, T., Gao, Y. T. 2000; 9 (12): 1335-1341

    Abstract

    We conducted a population-based case-control study in China to investigate whether body size plays a role in prostate cancer etiology and whether it can explain the rapid increase in prostate cancer incidence rates in China. A total of 238 cases newly diagnosed with primary prostate cancer in Shanghai, China, during 1993-1995 were included in the study. Four hundred and seventy-one healthy control subjects were randomly selected from among residents of Shanghai and frequency-matched to cases on the basis of age. In-person interviews were conducted to elicit information on height, weight history, and other lifestyle factors. Waist and hip circumferences were measured at interview. Odds ratios (ORs) were used to measure the association between prostate cancer and anthropometric variables including height, weight, body mass index (BMI), waist, hip, and right upper arm circumferences, and waist-to-hip ratio (WHR; an indicator of abdominal adiposity). High levels of WHR were related to an excess risk, with men in the highest quartile (WHR > 0.92) having an almost 3-fold risk (OR, 2.71; 95% CI = 1.66-4.41; Ptrend = 0.0001) compared with men in the lowest quartile (WHR < 0.86). In contrast, men in the highest quartile of hip circumference (>97.4 cm) had a reduced risk (OR, 0.46; 95% CI = 0.29-0.74; Ptrend = 0.0002) relative to men in the lowest quartile (<86 cm). No association was found for height, usual adult weight, or preadult and usual adult BMI. Our results suggest that even in a very lean population (average BMI = 21.9), abdominal adiposity may be associated with an increased risk of clinical prostate cancer, pointing to a role of hormones in prostate cancer etiology. Additional research is needed to confirm these findings in prospective studies, especially in Western populations where abdominal obesity is much more common, and to clarify the underlying hormonal mechanisms involved.

    View details for Web of Science ID 000166046900009

    View details for PubMedID 11142419

  • Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: A population-based case-control study in China CANCER RESEARCH Hsing, A. W., Gao, Y. T., Wu, G., Wang, X., Deng, J., Chen, Y. L., Sesterhenn, I. A., Mostofi, F. K., Benichou, J., Chang, C. S. 2000; 60 (18): 5111-5116

    Abstract

    The length of the polymorphic CAG trinucleotide repeat in the polyglutamine region of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Because increased androgenic activity has been linked to prostate cancer and because an ethnic variation exists in the CAG repeat length, this polymorphism has been suggested to explain part of the substantial racial difference in prostate cancer risk. We conducted a population-based case-control study in China to investigate whether CAG and other polymorphisms of the AR gene are associated with clinically significant prostate cancer in this low-risk population. Genomic DNA from 190 prostate cancer patients and 304 healthy controls was used for direct sequencing to evaluate the relationship of CAG and GGN (polyglycine) repeat length in the AR gene. Relative to western men, our study subjects had a longer CAG repeat length, with a median of 23 and only 10% of the subjects having a CAG repeat length shorter than 20. Men with a CAG repeat length shorter than 23 (median length) had a 65% increased risk of prostate cancer (odds ratio, 1.65; 95% confidence interval, 1.14-2.39), compared with men with a CAG repeat length of 23 or longer. For the GGN tract (GGT3GGG1GGT2GGCn), based on the sequencing results from 481 samples, we are the first to show that although GGC regions in the polyglycine tract are highly variable, there are no mutations or polymorphisms in the GGT and GGG regions. More than 72% of the subjects had a GGN repeat length of 23, and those with a GGN repeat length shorter than 23 had a 12% increased risk of prostate cancer (95% confidence interval, 0.71-1.78), compared with those with > or = 23 GGN repeats. Our study not only confirms that Chinese men do have a longer CAG repeat length than western men but also represents the first population-based study to show that even in a very low-risk population, a shorter CAG repeat length confers a higher risk of clinically significant prostate cancer. These results imply that CAG repeat length can potentially serve as a useful marker to identify a subset of individuals at higher risk of developing clinically significant prostate cancer. Larger studies are needed to evaluate the combined effect of CAG and GGN repeats. Because of the significance of AR in prostate cancer, investigation of factors that interact with the polyglutamine region of the AR gene to alter AR function and modulate prostate cancer risk is an important area for future research.

    View details for Web of Science ID 000089550600022

    View details for PubMedID 11016637

  • Case-control study of diet and prostate cancer in China CANCER CAUSES & CONTROL Lee, M. M., Wang, R. T., Hsing, A. W., Gu, F. L., Wang, T., Spitz, M. 1998; 9 (6): 545-552

    Abstract

    A higher incidence of prostate cancer is observed in the Western world than in Asian countries. Although it is relatively rare in China, an increased incidence has been reported in recent years. Studies in high-risk populations have suggested that dietary fat may play a role in enhancing the risk of developing prostate cancer. However, limited epidemiologic study has never examined the role of diet in low risk populations.A case-control study was conducted in 12 cities in China to evaluate the relationship between dietary factors and prostate cancer risk. We conducted personal interviews with 133 histopathologically confirmed prostate cancer cases diagnosed between 1989 to 1992 and 265 neighborhood controls of similar age.Cases were more likely than controls to consume food with high fat and from animal sources (p < 0.01). The daily fat intake and the percentage of energy from fat were statistically significantly higher among cases than among controls (p < 0.01). The adjusted odds ratio for total fat between lowest quartiles and highest quartiles was OR = 3.6 (95 percent C.I. 1.8-7.2); for saturated fat, OR = 2.9 (95 percent C.I. 1.5-5.7); and for unsaturated fat, OR = 3.3 (95 percent C.I. 1.7-6.3).The data suggest that dietary fat, both saturated and unsaturated, are associated with an increased risk for prostate cancer in a low risk population.

    View details for Web of Science ID 000078714300002

    View details for PubMedID 10189039

  • Risk factors for colorectal cancer in a prospective study among US white men INTERNATIONAL JOURNAL OF CANCER Hsing, A. W., McLaughlin, J. K., Chow, W. H., Schuman, L. M., Chien, H. T., Gridley, G., Bielke, E., Wacholder, S., Blot, W. J. 1998; 77 (4): 549-553

    Abstract

    The association of diet, smoking/drinking and occupation with subsequent risk of fatal colorectal cancer was investigated in a cohort of 17,633 white males aged 35 and older, who completed a mail questionnaire in 1966. During the subsequent 20 years of follow-up, 120 colon cancer and 25 rectal cancer deaths were identified. Due to small numbers, no significant dose-response trends were observed in the study, but risk of colon cancer was elevated among heavy cigarette smokers (> or = 30/day; RR = 2.3, 95% CI 0.9-5.7), heavy beer drinkers (> or = 14 times/month; RR = 1.9, 95% CI 1.0-3.8) and white-collar workers (RR = 1.7, 95% CI 1.0-3.0) or crafts workers within service and trade industries (RR = 2.6, 95% CI 1.1-5.8). In addition, an increased risk was seen for those who consumed red meat more than twice a day (RR = 1.8, 95% CI 0.8-4.4). Risk patterns for cancers of the colon and rectum combined were similar to those reported for cancer of the colon, but the estimates were somewhat dampened. Our findings support previous reports that a high intake of red meat and a sedentary life-style may increase the risk of colon cancer.

    View details for Web of Science ID 000074932500013

    View details for PubMedID 9679757

  • VASECTOMY AND PROSTATE-CANCER RISK IN CHINA CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hsing, A. W., Wang, R. T., Gu, F. L., Lee, M., Wang, T., Leng, T. J., Spitz, M., Blot, W. J. 1994; 3 (4): 285-288

    Abstract

    Vasectomy has been reported to be associated with an increased risk of prostate cancer in western countries. A hospital-based case-control study was conducted in 12 cities in China to evaluate the relationship between vasectomy and prostate cancer risk in China, a low-risk country with rising incidence and increasing use of vasectomy. Interviews were conducted with 138 histologically confirmed prostate cancer cases diagnosed during 1989-1992 and 638 controls (158 hospital cancer, 158 hospital noncancer, and 322 neighborhood controls) of similar ages. Vasectomy at least 10 years prior to interview was reported by 10% of the cases versus 3% of the controls. Odds ratios for prostate cancer associated with vasectomy were 2.0 (95% confidence interval, 0.7-6.1), 3.3 (95% confidence interval, 1.0-11.3), and 6.7 (95% confidence interval, 2.1-21.6), respectively, when hospital cancer, hospital noncancer, and neighborhood controls were used for comparison. Although detection bias is of concern, the data suggest that in China, men with a history of vasectomy may experience an increased risk of prostate cancer.

    View details for Web of Science ID A1994NR18900001

    View details for PubMedID 8061575

  • CIGARETTE-SMOKING AND CANCERS OF THE RENAL PELVIS AND URETER CANCER RESEARCH McLaughlin, J. K., Silverman, D. T., Hsing, A. W., Ross, R. K., Schoenberg, J. B., Yu, M. C., Stemhagen, A., Lynch, C. F., Blot, W. J., Fraumeni, J. F. 1992; 52 (2): 254-257

    Abstract

    A population-based case-control study of renal pelvis and ureter cancers (502 cases, 496 controls) conducted in three areas of the United States found cigarette smoking to be associated with a 3.1-fold increase in risk, with long-term (greater than 45 years) smokers having a 7.2-fold increased risk. Statistically significant dose-response associations were observed for both cancer sites and in both sexes regardless of the measure used: cigarettes per day, duration of use, or pack years. A significant decreasing trend in risk with increasing years quit smoking was also demonstrated for these cancers. Attributable risk estimates indicate that approximately 7 of 10 cancers of the renal pelvis and ureter among men and almost 4 of 10 among women are caused by smoking. The results of this study, the largest to date, confirm that cigarette smoking is the major cause of cancers of the renal pelvis and ureter, and that cessation of smoking could eliminate a large proportion of these tumors.

    View details for Web of Science ID A1992GZ69300002

    View details for PubMedID 1728398