Linda Kachuri

All Publications

• Genetically adjusted PSA levels for prostate cancer screening. Nature medicine Kachuri, L., Hoffmann, T. J., Jiang, Y., Berndt, S. I., Shelley, J. P., Schaffer, K. R., Machiela, M. J., Freedman, N. D., Huang, W. Y., Li, S. A., Easterlin, R., Goodman, P. J., Till, C., Thompson, I., Lilja, H., Van Den Eeden, S. K., Chanock, S. J., Haiman, C. A., Conti, D. V., Klein, R. J., Mosley, J. D., Graff, R. E., Witte, J. S. 2023

  Abstract

  Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGSPSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10-14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10-12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.

  View details for DOI 10.1038/s41591-023-02277-9

  View details for PubMedID 37264206

  View details for PubMedCentralID 424236

• Gene expression in African Americans, Puerto Ricans and Mexican Americans reveals ancestry-specific patterns of genetic architecture. Nature genetics Kachuri, L., Mak, A. C., Hu, D., Eng, C., Huntsman, S., Elhawary, J. R., Gupta, N., Gabriel, S., Xiao, S., Keys, K. L., Oni-Orisan, A., Rodríguez-Santana, J. R., LeNoir, M. A., Borrell, L. N., Zaitlen, N. A., Williams, L. K., Gignoux, C. R., Burchard, E. G., Ziv, E. 2023

  Abstract

  We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.

  View details for DOI 10.1038/s41588-023-01377-z

  View details for PubMedID 37231098

  View details for PubMedCentralID 7737656

• Genetic determinants of blood-cell traits influence susceptibility to childhood acute lymphoblastic leukemia. American journal of human genetics Kachuri, L., Jeon, S., DeWan, A. T., Metayer, C., Ma, X., Witte, J. S., Chiang, C. W., Wiemels, J. L., de Smith, A. J. 2021; 108 (10): 1823-1835

  Abstract

  Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood-cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of childhood ALL (2,666 affected individuals, 60,272 control individuals) and a multi-trait GWAS of nine blood-cell indices in the UK Biobank. We identified 3,000 blood-cell-trait-associated (p < 5.0 × 10-8) variants, explaining 4.0% to 23.9% of trait variation and including 115 loci associated with blood-cell ratios (LMR, lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio). ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, p = 4.0 × 10-4) and PLR (rg = -0.072, p = 0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (odds ratio [OR] = 1.16, p = 0.031) and strengthened after accounting for other cell types (OR = 1.43, p = 8.8 × 10-4). We observed positive associations with increasing LMR (OR = 1.22, p = 0.0017) and inverse effects for NLR (OR = 0.67, p = 3.1 × 10-4) and PLR (OR = 0.80, p = 0.002). Our study shows that a genetically induced shift toward higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.

  View details for DOI 10.1016/j.ajhg.2021.08.004

  View details for PubMedID 34469753

  View details for PubMedCentralID PMC8546033

• Pan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction. Nature communications Kachuri, L., Graff, R. E., Smith-Byrne, K., Meyers, T. J., Rashkin, S. R., Ziv, E., Witte, J. S., Johansson, M. 2020; 11 (1): 6084

  Abstract

  Cancer risk is determined by a complex interplay of environmental and heritable factors. Polygenic risk scores (PRS) provide a personalized genetic susceptibility profile that may be leveraged for disease prediction. Using data from the UK Biobank (413,753 individuals; 22,755 incident cancer cases), we quantify the added predictive value of integrating cancer-specific PRS with family history and modifiable risk factors for 16 cancers. We show that incorporating PRS measurably improves prediction accuracy for most cancers, but the magnitude of this improvement varies substantially. We also demonstrate that stratifying on levels of PRS identifies significantly divergent 5-year risk trajectories after accounting for family history and modifiable risk factors. At the population level, the top 20% of the PRS distribution accounts for 4.0% to 30.3% of incident cancer cases, exceeding the impact of many lifestyle-related factors. In summary, this study illustrates the potential for improving cancer risk assessment by integrating genetic risk scores.

  View details for DOI 10.1038/s41467-020-19600-4

  View details for PubMedID 33247094

  View details for PubMedCentralID PMC7695829

• Association of immunoglobulin E levels with glioma risk and survival. Journal of the National Cancer Institute Guerra, G., Nakase, T., Kachuri, L., McCoy, L., Hansen, H. M., Rice, T., Wiemels, J. L., Wiencke, J. K., Molinaro, A. M., Wrensch, M., Francis, S. S. 2024

  Abstract

  Previous epidemiologic studies have reported an association of serum immunoglobulin E (IgE) levels with reduced glioma risk, but the association between IgE and glioma prognosis has not been characterized. This study aimed to examine how sex, tumor subtype, and IgE class modulate the association of serum IgE levels with glioma risk and survival.We conducted a case-control study using participants from the University of California, San Francisco Adult Glioma Study (1997-2010). Serum IgE levels for total, respiratory and food allergy were measured in adults diagnosed with glioma (n = 1319) and cancer-free controls (n = 1139) matched based on age, sex, and race and ethnicity. Logistic regression was adjusted for patient demographics to assess the association between IgE levels and glioma risk. Multivariable Cox regression adjusted for patient-specific and tumor-specific factors compared survival between the elevated and normal IgE groups. All statistical tests were 2-sided.Elevated total IgE was associated with reduced risk of IDH-wildtype (RR = 0.78, 95% CI: 0.71-0.86) and IDH-mutant glioma (RR = 0.73, 95% CI: 0.63-0.85). In multivariable Cox regression, positive respiratory IgE was associated with improved survival for IDH-wildtype glioma (RR = 0.79, 95% CI: 0.67-0.93). The reduction in mortality risk was significant in females only (RR = 0.75, 95% CI: 0.57-0.98) with an improvement in median survival of 6.9 months (P<.001).Elevated serum IgE was associated with improved prognosis for IDH-wildtype glioma, with a more pronounced protective effect in females than males, which has implications for the future study of IgE-based immunotherapies for glioma.

  View details for DOI 10.1093/jnci/djae265

  View details for PubMedID 39447063

• Polygenic score for body mass index in relation to mortality among patients with renal cell cancer. International journal of obesity (2005) Deng, Z., Graff, R. E., Batai, K., Chung, B. I., Langston, M. E., Kachuri, L. 2024

  Abstract

  The association between body mass index (BMI) and mortality among individuals with renal cell cancer (RCC) is debated, with some observational studies suggesting a lower mortality associated with higher BMI. However, methodological issues such as confounding and reverse causation may bias these findings. Using BMI-associated genetic variants can avoid these biases and generate more valid estimates.In this prospective cohort study, we included 1264 RCC patients (446 deaths) from the UK Biobank. We created a BMI polygenic score (PGS) based on 336 BMI-associated genetic variants. The association between the PGS and mortality (all-cause and RCC-specific) was evaluated by logistic regression (all RCC cases) and Cox regression (906 incident cases). For comparison, the associations of measured pre-diagnostic BMI and waist-to-hip ratio (WHR) with mortality were quantified by Cox regression among incident cases. We stratified these analyses by time between anthropometric measurement and RCC diagnosis to assess the influence of reverse causation.We did not observe an association between the BMI PGS and all-cause mortality among RCC patients (hazard ratio (HR) per SD increase = 0.98, 95% CI: 0.88,1.10). No association was found for pre-diagnostic BMI (HR per 5 kg/m2 increase = 0.93, 95% CI: 0.83,1.04) or WHR (HR per 0.1 increase = 0.97, 95% CI: 0.83,1.13) with mortality. In patients with anthropometrics measured within 2 years before RCC diagnosis, we observed associations of higher BMI (HR per 5 kg/m2 = 0.76, 95% CI: 0.59,0.98) and WHR (HR = 0.67 per 0.1 increase, 95% CI: 0.45,0.98) with a lower risk of death. Similar patterns were observed for RCC-specific mortality.We found no association between either genetic variants for high BMI or measured pre-diagnostic body adiposity and mortality among RCC patients, and our results suggested a role for reverse causation in the association of obesity with lower mortality. Future studies should be designed carefully to produce unbiased estimates that account for confounding and reverse causation.

  View details for DOI 10.1038/s41366-024-01609-0

  View details for PubMedID 39152336

  View details for PubMedCentralID 6221676

• Genetic relations between type 1 diabetes, coronary artery disease and leukocyte counts. Diabetologia Adebekun, J., Nadig, A., Saarah, P., Asgari, S., Kachuri, L., Alagpulinsa, D. A. 2024

  Abstract

  AIMS/HYPOTHESIS: Type 1 diabetes is associated with excess coronary artery disease (CAD) risk even when known cardiovascular risk factors are accounted for. Genetic perturbation of haematopoiesis that alters leukocyte production is a novel independent modifier of CAD risk. We examined whether there are shared genetic determinants and causal relationships between type 1 diabetes, CAD and leukocyte counts.METHODS: Genome-wide association study summary statistics were used to perform pairwise linkage disequilibrium score regression and heritability estimation from summary statistics (rho-HESS) to respectively estimate the genome-wide and local genetic correlations, and two-sample Mendelian randomisation to estimate the causal relationships between leukocyte counts (335,855 healthy individuals), type 1 diabetes (18,942 cases, 501,638 control individuals) and CAD (122,733 cases, 424,528 control individuals). A latent causal variable (LCV) model was performed to estimate the genetic causality proportion of the genetic correlation between type 1 diabetes and CAD.RESULTS: There was significant genome-wide genetic correlation (rg) between type 1 diabetes and CAD (rg=0.088, p=8.60 * 10-3) and both diseases shared significant genome-wide genetic determinants with eosinophil count (rg for type 1 diabetes [rg(T1D)]=0.093, p=7.20 * 10-3, rg for CAD [rg(CAD)]=0.092, p=3.68 * 10-6) and lymphocyte count (rg(T1D)=-0.052, p=2.76 * 10-2, rg(CAD)=0.176, p=1.82 * 10-15). Sixteen independent loci showed stringent Bonferroni significant local genetic correlations between leukocyte counts, type 1 diabetes and/or CAD. Cis-genetic regulation of the expression levels of genes within shared loci between type 1 diabetes and CAD was associated with both diseases as well as leukocyte counts, including SH2B3, CTSH, MORF4L1, CTRB1, CTRB2, CFDP1 and IFIH1. Genetically predicted lymphocyte, neutrophil and eosinophil counts were associated with type 1 diabetes and CAD (lymphocyte OR for type 1 diabetes [ORT1D]=0.67, p=2.02-19, ORCAD=1.09, p=2.67 * 10-6; neutrophil ORT1D=0.82, p=5.63 * 10-5, ORCAD=1.17, p=5.02 * 10-14; and eosinophil ORT1D=1.67, p=5.45 * 10-25, ORCAD=1.07, p=2.03 * 10-4. The genetic causality proportion between type 1 diabetes and CAD was 0.36 ± 0.16 (pLCV=1.30 * 10-2), suggesting a possible intermediary causal variable.CONCLUSIONS/INTERPRETATION: This study sheds light on shared genetic mechanisms underlying type 1 diabetes and CAD, which may contribute to their co-occurrence through regulation of gene expression and leukocyte counts and identifies cellular and molecular targets for further investigation for disease prediction and potential drug discovery.

  View details for DOI 10.1007/s00125-024-06247-9

  View details for PubMedID 39141130

• Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes. Neuro-oncology Nakase, T., Guerra, G. A., Ostrom, Q. T., Ge, T., Melin, B. S., Wrensch, M., Wiencke, J. K., Jenkins, R. B., Eckel-Passow, J. E., Bondy, M. L., Francis, S. S., Kachuri, L. 2024

  Abstract

  Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to efficiently capture genetic risk using available data.We applied a method based on continuous shrinkage priors (PRS-CS) to model the joint effects of over 1 million common variants on disease risk and compared this to an approach (PRS-CT) that only selects a limited set of independent variants that reach genome-wide significance (P<5×10-8). PRS models were trained using GWAS stratified by histological (10,346 cases, 14,687 controls) and molecular subtype (2,632 cases, 2,445 controls), and validated in two independent cohorts.PRS-CS was generally more predictive than PRS-CT with a median increase in explained variance (R2) of 24% (interquartile range=11-30%) across glioma subtypes. Improvements were pronounced for glioblastoma (GBM), with PRS-CS yielding larger odds ratios (OR) per standard deviation (OR=1.93, P=2.0×10-54 vs. OR=1.83, P=9.4×10-50) and higher explained variance (R2=2.82% vs. R2=2.56%). Individuals in the 80th percentile of the PRS-CS distribution had significantly higher risk of GBM (0.107%) at age 60 compared to those with average PRS (0.046%, P=2.4×10-12). Lifetime absolute risk reached 1.18% for glioma and 0.76% for IDH wildtype tumors for individuals in the 95th PRS percentile. PRS-CS augmented the classification of IDH mutation status in cases when added to demographic factors (AUC=0.839 vs. AUC=0.895, PΔAUC=6.8×10-9).Genome-wide PRS has potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes.

  View details for DOI 10.1093/neuonc/noae112

  View details for PubMedID 38916140

• Ambient air pollution and urological cancer risk: A systematic review and meta-analysis of epidemiological evidence. Nature communications Li, J., Deng, Z., Soerensen, S. J., Kachuri, L., Cardenas, A., Graff, R. E., Leppert, J. T., Langston, M. E., Chung, B. I. 2024; 15 (1): 5116

  Abstract

  Exposure to ambient air pollution has significant adverse health effects; however, whether air pollution is associated with urological cancer is largely unknown. We conduct a systematic review and meta-analysis with epidemiological studies, showing that a 5 μg/m3 increase in PM2.5 exposure is associated with a 6%, 7%, and 9%, increased risk of overall urological, bladder, and kidney cancer, respectively; and a 10 μg/m3 increase in NO2 is linked to a 3%, 4%, and 4% higher risk of overall urological, bladder, and prostate cancer, respectively. Were these associations to reflect causal relationships, lowering PM2.5 levels to 5.8 μg/m3 could reduce the age-standardized rate of urological cancer by 1.5 ~ 27/100,000 across the 15 countries with the highest PM2.5 level from the top 30 countries with the highest urological cancer burden. Implementing global health policies that can improve air quality could potentially reduce the risk of urologic cancer and alleviate its burden.

  View details for DOI 10.1038/s41467-024-48857-2

  View details for PubMedID 38879581

  View details for PubMedCentralID PMC11180144

• Transcriptome-Wide Association Analysis Identifies Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer. HGG advances Chen, D. M., Dong, R., Kachuri, L., Hoffmann, T., Jiang, Y., Berndt, S. I., Shelley, J. P., Schaffer, K. R., Machiela, M. J., Freedman, N. D., Huang, W. Y., Li, S. A., Lilja, H., Justice, A., Madduri, R., Rodriguez, A., Van Den Eeden, S. K., Chanock, S., Haiman, C. A., Conti, D. V., Klein, R. J., Mosley, J. D., Witte, J. S., Graff, R. E. 2024: 100315

  Abstract

  Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10×10-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61×10-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25×10-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single-tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a genome-wide association study (GWAS). Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability > 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

  View details for DOI 10.1016/j.xhgg.2024.100315

  View details for PubMedID 38845201

• The full spectrum of SLC22 OCT1 mutations illuminates the bridge between drug transporter biophysics and pharmacogenomics. Molecular cell Yee, S. W., Macdonald, C. B., Mitrovic, D., Zhou, X., Koleske, M. L., Yang, J., Buitrago Silva, D., Rockefeller Grimes, P., Trinidad, D. D., More, S. S., Kachuri, L., Witte, J. S., Delemotte, L., Giacomini, K. M., Coyote-Maestas, W. 2024

  Abstract

  Mutations in transporters can impact an individual's response to drugs and cause many diseases. Few variants in transporters have been evaluated for their functional impact. Here, we combine saturation mutagenesis and multi-phenotypic screening to dissect the impact of 11,213 missense single-amino-acid deletions, and synonymous variants across the 554 residues of OCT1, a key liver xenobiotic transporter. By quantifying in parallel expression and substrate uptake, we find that most variants exert their primary effect on protein abundance, a phenotype not commonly measured alongside function. Using our mutagenesis results combined with structure prediction and molecular dynamic simulations, we develop accurate structure-function models of the entire transport cycle, providing biophysical characterization of all known and possible human OCT1 polymorphisms. This work provides a complete functional map of OCT1 variants along with a framework for integrating functional genomics, biophysical modeling, and human genetics to predict variant effects on disease and drug efficacy.

  View details for DOI 10.1016/j.molcel.2024.04.008

  View details for PubMedID 38703769

• Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis. Nature communications Middha, P., Thummalapalli, R., Betti, M. J., Yao, L., Quandt, Z., Balaratnam, K., Bejan, C. A., Cardenas, E., Falcon, C. J., Faleck, D. M., Gubens, M. A., Huntsman, S., Johnson, D. B., Kachuri, L., Khan, K., Li, M., Lovly, C. M., Murray, M. H., Patel, D., Werking, K., Xu, Y., Zhan, L. J., Balko, J. M., Liu, G., Aldrich, M. C., Schoenfeld, A. J., Ziv, E. 2024; 15 (1): 2568

  Abstract

  Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10-03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10-04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

  View details for DOI 10.1038/s41467-023-44512-4

  View details for PubMedID 38531883

  View details for PubMedCentralID PMC10966072

• A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children. Cell genomics de Smith, A. J., Wahlster, L., Jeon, S., Kachuri, L., Black, S., Langie, J., Cato, L. D., Nakatsuka, N., Chan, T. F., Xia, G., Mazumder, S., Yang, W., Gazal, S., Eng, C., Hu, D., Burchard, E. G., Ziv, E., Metayer, C., Mancuso, N., Yang, J. J., Ma, X., Wiemels, J. L., Yu, F., Chiang, C. W., Sankaran, V. G. 2024: 100526

  Abstract

  Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry, showed evidence of selection in human history, and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children.

  View details for DOI 10.1016/j.xgen.2024.100526

  View details for PubMedID 38537633

• Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants. Nature genetics Wang, A., Shen, J., Rodriguez, A. A., Saunders, E. J., Chen, F., Janivara, R., Darst, B. F., Sheng, X., Xu, Y., Chou, A. J., Benlloch, S., Dadaev, T., Brook, M. N., Plym, A., Sahimi, A., Hoffman, T. J., Takahashi, A., Matsuda, K., Momozawa, Y., Fujita, M., Laisk, T., Figuerêdo, J., Muir, K., Ito, S., Liu, X., Uchio, Y., Kubo, M., Kamatani, Y., Lophatananon, A., Wan, P., Andrews, C., Lori, A., Choudhury, P. P., Schleutker, J., Tammela, T. L., Sipeky, C., Auvinen, A., Giles, G. G., Southey, M. C., MacInnis, R. J., Cybulski, C., Wokolorczyk, D., Lubinski, J., Rentsch, C. T., Cho, K., Mcmahon, B. H., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bojesen, S. E., Røder, A., Stroomberg, H. V., Batra, J., Chambers, S., Horvath, L., Clements, J. A., Tilly, W., Risbridger, G. P., Gronberg, H., Aly, M., Szulkin, R., Eklund, M., Nordstrom, T., Pashayan, N., Dunning, A. M., Ghoussaini, M., Travis, R. C., Key, T. J., Riboli, E., Park, J. Y., Sellers, T. A., Lin, H. Y., Albanes, D., Weinstein, S., Cook, M. B., Mucci, L. A., Giovannucci, E., Lindstrom, S., Kraft, P., Hunter, D. J., Penney, K. L., Turman, C., Tangen, C. M., Goodman, P. J., Thompson, I. M., Hamilton, R. J., Fleshner, N. E., Finelli, A., Parent, M. É., Stanford, J. L., Ostrander, E. A., Koutros, S., Beane Freeman, L. E., Stampfer, M., Wolk, A., Håkansson, N., Andriole, G. L., Hoover, R. N., Machiela, M. J., Sørensen, K. D., Borre, M., Blot, W. J., Zheng, W., Yeboah, E. D., Mensah, J. E., Lu, Y. J., Zhang, H. W., Feng, N., Mao, X., Wu, Y., Zhao, S. C., Sun, Z., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., West, C. M., Barnett, G., Maier, C., Schnoeller, T., Luedeke, M., Kibel, A. S., Drake, B. F., Cussenot, O., Cancel-Tassin, G., Menegaux, F., Truong, T., Koudou, Y. A., John, E. M., Grindedal, E. M., Maehle, L., Khaw, K. T., Ingles, S. A., Stern, M. C., Vega, A., Gómez-Caamaño, A., Fachal, L., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Teixeira, M. R., Paulo, P., Brandão, A., Watya, S., Lubwama, A., Bensen, J. T., Butler, E. N., Mohler, J. L., Taylor, J. A., Kogevinas, M., Dierssen-Sotos, T., Castaño-Vinyals, G., Cannon-Albright, L., Teerlink, C. C., Huff, C. D., Pilie, P., Yu, Y., Bohlender, R. J., Gu, J., Strom, S. S., Multigner, L., Blanchet, P., Brureau, L., Kaneva, R., Slavov, C., Mitev, V., Leach, R. J., Brenner, H., Chen, X., Holleczek, B., Schöttker, B., Klein, E. A., Hsing, A. W., Kittles, R. A., Murphy, A. B., Logothetis, C. J., Kim, J., Neuhausen, S. L., Steele, L., Ding, Y. C., Isaacs, W. B., Nemesure, B., Hennis, A. J., Carpten, J., Pandha, H., Michael, A., De Ruyck, K., De Meerleer, G., Ost, P., Xu, J., Razack, A., Lim, J., Teo, S. H., Newcomb, L. F., Lin, D. W., Fowke, J. H., Neslund-Dudas, C. M., Rybicki, B. A., Gamulin, M., Lessel, D., Kulis, T., Usmani, N., Abraham, A., Singhal, S., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Gago-Dominguez, M., Castelao, J. E., Martinez, M. E., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Bush, W. S., Aldrich, M. C., Crawford, D. C., Srivastava, S., Cullen, J., Petrovics, G., Casey, G., Wang, Y., Tettey, Y., Lachance, J., Tang, W., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Yamoah, K., Govindasami, K., Chokkalingam, A. P., Keaton, J. M., Hellwege, J. N., Clark, P. E., Jalloh, M., Gueye, S. M., Niang, L., Ogunbiyi, O., Shittu, O., Amodu, O., Adebiyi, A. O., Aisuodionoe-Shadrach, O. I., Ajibola, H. O., Jamda, M. A., Oluwole, O. P., Nwegbu, M., Adusei, B., Mante, S., Darkwa-Abrahams, A., Diop, H., Gundell, S. M., Roobol, M. J., Jenster, G., van Schaik, R. H., Hu, J. J., Sanderson, M., Kachuri, L., Varma, R., McKean-Cowdin, R., Torres, M., Preuss, M. H., Loos, R. J., Zawistowski, M., Zöllner, S., Lu, Z., Van Den Eeden, S. K., Easton, D. F., Ambs, S., Edwards, T. L., Mägi, R., Rebbeck, T. R., Fritsche, L., Chanock, S. J., Berndt, S. I., Wiklund, F., Nakagawa, H., Witte, J. S., Gaziano, J. M., Justice, A. C., Mancuso, N., Terao, C., Eeles, R. A., Kote-Jarai, Z., Madduri, R. K., Conti, D. V., Haiman, C. A. 2023

  Abstract

  The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

  View details for DOI 10.1038/s41588-023-01534-4

  View details for PubMedID 37945903

  View details for PubMedCentralID 8148035

• Clinical consequences of a genetic predisposition toward higher benign prostate-specific antigen levels. EBioMedicine Shi, M., Shelley, J. P., Schaffer, K. R., Tosoian, J. J., Bagheri, M., Witte, J. S., Kachuri, L., Mosley, J. D. 2023; 97: 104838

  Abstract

  Prostate-specific antigen (PSA) levels are influenced by genetic variation unrelated to prostate cancer risk. Whether a genetic predisposition to a higher PSA level predisposes to a diagnostic work-up for prostate cancer is not known.Participants were 3110 men of African and European ancestries ages 45-70, without prostate cancer and with a baseline PSA < 4 ng/mL, undergoing routine clinical PSA screening. The exposure was a polygenic score (PGS) comprising 111 single nucleotide polymorphisms associated with PSA level, but not prostate cancer. We tested whether the PGS was associated with a: 1) PSA value > 4 ng/mL, 2) International Classification of Diseases (ICD) code for an elevated PSA, 3) encounter with a urologist, or 4) prostate biopsy. Multivariable Cox proportional hazards models were adjusted for age and genetic principal components. Analyses were stratified by age (45-59 years, and 60-70 years old). Association estimates are per standard deviation change in the PGS.The median age was 56.6 years, and 2118 (68%) participants were 45-59 years. The median (IQR) baseline PSA level was 1.0 (0.6-1.7) ng/mL. Among men ages 45-59, the PGS was associated with a PSA > 4 (hazard ratio [HR] = 1.35 [95% CI, 1.17-1.57], p = 4.5 × 10-5), an ICD code for elevated PSA (HR = 1.30 [1.12-1.52], p = 8.0 × 10-4), a urological evaluation (HR = 1.34 [1.14-1.57], p = 4.8 × 10-4), and undergoing a prostate biopsy (HR = 1.35 [1.11-1.64], p = 0.002). Among men ages 60-70, association effect sizes were smaller and not significant.A predisposition toward higher PSA levels was associated with clinical evaluations of an elevated PSA among men ages 45-59 years.National Institutes of Health (NIH).

  View details for DOI 10.1016/j.ebiom.2023.104838

  View details for PubMedID 37865044

• Principles and methods for transferring polygenic risk scores across global populations. Nature reviews. Genetics Kachuri, L., Chatterjee, N., Hirbo, J., Schaid, D. J., Martin, I., Kullo, I. J., Kenny, E. E., Pasaniuc, B., Witte, J. S., Ge, T. 2023

  Abstract

  Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.

  View details for DOI 10.1038/s41576-023-00637-2

  View details for PubMedID 37620596

  View details for PubMedCentralID 9391275

• Inherited polymorphisms in the Human Leukocyte Antigen Region modify the association between varicella-zoster virus antibody reactivity and glioma prognosis. Neuro-oncology Francis, S. S., Guerra, G., Hansen, H. M., Wendt, G., Kachuri, L., Wiencke, J. K., Wrensch, M. 2023

  View details for DOI 10.1093/neuonc/noad122

  View details for PubMedID 37595256

• Development and testing of a polygenic risk score for breast cancer aggressiveness. NPJ precision oncology Shieh, Y., Roger, J., Yau, C., Wolf, D. M., Hirst, G. L., Swigart, L. B., Huntsman, S., Hu, D., Nierenberg, J. L., Middha, P., Heise, R. S., Shi, Y., Kachuri, L., Zhu, Q., Yao, S., Ambrosone, C. B., Kwan, M. L., Caan, B. J., Witte, J. S., Kushi, L. H., 't Veer, L. v., Esserman, L. J., Ziv, E. 2023; 7 (1): 42

  Abstract

  Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS's association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06-1.21, p = 4.0 × 10-4). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+). Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.

  View details for DOI 10.1038/s41698-023-00382-z

  View details for PubMedID 37188791

  View details for PubMedCentralID PMC10185660

• Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome. eLife Cortez Cardoso Penha, R., Smith-Byrne, K., Atkins, J. R., Haycock, P. C., Kar, S., Codd, V., Samani, N. J., Nelson, C., Milojevic, M., Gabriel, A. A., Amos, C., Brennan, P., Hung, R. J., Kachuri, L., Mckay, J. D. 2023; 12

  Abstract

  Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours.We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343).Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity.This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17-022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).

  View details for DOI 10.7554/eLife.83118

  View details for PubMedID 37079368

  View details for PubMedCentralID PMC10118386

• A Polygenic Risk Score for Prostate Cancer Risk Prediction. JAMA internal medicine Schaffer, K. R., Shi, M., Shelley, J. P., Tosoian, J. J., Kachuri, L., Witte, J. S., Mosley, J. D. 2023

  Abstract

  This retrospective cohort study compares 2 risk calculator systems that compute the probabilities of finding high-grade or any cancer on biopsy results in men undergoing a first prostate biopsy.

  View details for DOI 10.1001/jamainternmed.2022.6795

  View details for PubMedID 36877498

• Inverted genomic regions between reference genome builds in humans impact imputation accuracy and decrease the power of association testing. HGG advances Sheng, X., Xia, L., Cahoon, J. L., Conti, D. V., Haiman, C. A., Kachuri, L., Chiang, C. W. 2023; 4 (1): 100159

  Abstract

  Over the last two decades, the human reference genome has undergone multiple updates as we complete a linear representation of our genome. Two versions of human references are currently used in the biomedical literature, GRCh37/hg19 and GRCh38. Conversions between these versions are critical for quality control, imputation, and association analysis. In the present study, we show that single-nucleotide variants (SNVs) in regions inverted between different builds of the reference genome are often mishandled bioinformatically. Depending on the array type, SNVs are found in approximately 2-5 Mb of the genome that are inverted between reference builds. Coordinate conversions of these variants are mishandled by both the TOPMed imputation server as well as routine in-house quality control pipelines, leading to underrecognized downstream analytical consequences. Specifically, we observe that undetected allelic conversion errors for palindromic (i.e., A/T or C/G) variants in these inverted regions would destabilize the local haplotype structure, leading to loss of imputation accuracy and power in association analyses. Though only a small proportion of the genome is affected, these regions include important disease susceptibility variants that would be affected. For example, the p value of a known locus associated with prostate cancer on chromosome 10 (chr10) would drop from 2.86 × 10-7 to 0.0011 in a case-control analysis of 20,286 Africans and African Americans (10,643 cases and 9,643 controls). We devise a straight-forward heuristic based on the popular tool, liftOver, that can easily detect and correct these variants in the inverted regions between genome builds to locally improve imputation accuracy.

  View details for DOI 10.1016/j.xhgg.2022.100159

  View details for PubMedID 36465187

  View details for PubMedCentralID PMC9709082

• Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies. BMC medicine Cavazos, T. B., Kachuri, L., Graff, R. E., Nierenberg, J. L., Thai, K. K., Alexeeff, S., Van Den Eeden, S., Corley, D. A., Kushi, L. H., Hoffmann, T. J., Ziv, E., Habel, L. A., Jorgenson, E., Sakoda, L. C., Witte, J. S. 2022; 20 (1): 332

  Abstract

  Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored.To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers.We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer.Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.

  View details for DOI 10.1186/s12916-022-02535-6

  View details for PubMedID 36199081

• Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer. Nature genetics Byun, J., Han, Y., Li, Y., Xia, J., Long, E., Choi, J., Xiao, X., Zhu, M., Zhou, W., Sun, R., Bossé, Y., Song, Z., Schwartz, A., Lusk, C., Rafnar, T., Stefansson, K., Zhang, T., Zhao, W., Pettit, R. W., Liu, Y., Li, X., Zhou, H., Walsh, K. M., Gorlov, I., Gorlova, O., Zhu, D., Rosenberg, S. M., Pinney, S., Bailey-Wilson, J. E., Mandal, D., de Andrade, M., Gaba, C., Willey, J. C., You, M., Anderson, M., Wiencke, J. K., Albanes, D., Lam, S., Tardon, A., Chen, C., Goodman, G., Bojeson, S., Brenner, H., Landi, M. T., Chanock, S. J., Johansson, M., Muley, T., Risch, A., Wichmann, H. E., Bickeböller, H., Christiani, D. C., Rennert, G., Arnold, S., Field, J. K., Shete, S., Le Marchand, L., Melander, O., Brunnstrom, H., Liu, G., Andrew, A. S., Kiemeney, L. A., Shen, H., Zienolddiny, S., Grankvist, K., Johansson, M., Caporaso, N., Cox, A., Hong, Y. C., Yuan, J. M., Lazarus, P., Schabath, M. B., Aldrich, M. C., Patel, A., Lan, Q., Rothman, N., Taylor, F., Kachuri, L., Witte, J. S., Sakoda, L. C., Spitz, M., Brennan, P., Lin, X., McKay, J., Hung, R. J., Amos, C. I. 2022

  Abstract

  To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

  View details for DOI 10.1038/s41588-022-01115-x

  View details for PubMedID 35915169

• The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival. American journal of human genetics Guerra, G., Kachuri, L., Wendt, G., Hansen, H. M., Mack, S. J., Molinaro, A. M., Rice, T., Bracci, P., Wiencke, J. K., Kasahara, N., Eckel-Passow, J. E., Jenkins, R. B., Wrensch, M., Francis, S. S. 2022

  Abstract

  Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study, we leveraged genetic predictors of antibody response to 12 viral antigens to investigate the relationship with glioma risk and survival. Genetic reactivity scores (GRSs) for each antigen were derived from genome-wide-significant (p < 5 × 10-8) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution by using data from 3,418 glioma-affected individuals subtyped by somatic mutations and 8,156 controls. Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were associated with glioma risk and survival (Bonferroni-corrected p < 0.01). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild-type gliomas (ORZEBRA = 0.91, p = 0.0099/ORMCV = 1.11, p = 0.0054). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR = 1.09, p = 0.040) and improved survival (HR = 0.86, p = 0.010). HLA-DQA1∗03:01 was significantly associated with decreased risk of glioma overall (OR = 0.85, p = 3.96 × 10-4) after multiple testing adjustment. This systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may inform applications of antiviral-based therapies in glioma treatment.

  View details for DOI 10.1016/j.ajhg.2022.04.011

  View details for PubMedID 35550063

• Genetic analysis of lung cancer and the germline impact on somatic mutation burden. Journal of the National Cancer Institute Gabriel, A. A., Atkins, J. R., Penha, R. C., Smith-Byrne, K., Gaborieau, V., Voegele, C., Abedi-Ardekani, B., Milojevic, M., Olaso, R., Meyer, V., Boland, A., Deleuze, J. F., Zaridze, D., Mukeriya, A., Swiatkowska, B., Janout, V., Schejbalová, M., Mates, D., Stojšić, J., Ognjanovic, M., Witte, J. S., Rashkin, S. R., Kachuri, L., Hung, R. J., Kar, S., Brennan, P., Sertier, A. S., Ferrari, A., Viari, A., Johansson, M., Amos, C. I., Foll, M., McKay, J. D. 2022

  Abstract

  Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking propensity and DNA repair genes, but further work is required to identify susceptibility variants.To identify LC susceptibility loci, a family history-based genome-wide association (GWAx) study of LC (48,843 European "proxy" LC cases, 195,387 controls) was combined with previously LC GWAS (29,266 cases, 56,450 controls) by meta-analysis. Colocalisation was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic Risk Scores (PRS) were tested within an independent validation cohort (1,666 LC cases vs 6,664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumour resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided.The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1) and smoking propensity (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as sub-genome wide significant variants related to eQTLs and/or smoking propensity, assisted in LC genetic risk prediction (OR = 1.37, 95% CI 1.29-1.45, P = 1.44 x10-25). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumours.This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.

  View details for DOI 10.1093/jnci/djac087

  View details for PubMedID 35511172

• Long telomeres in need of a SNP: Germline contributions of telomere maintenance to glioma. Neuro-oncology Kachuri, L., Walsh, K. M. 2022; 24 (2): 182-183

  View details for DOI 10.1093/neuonc/noab260

  View details for PubMedID 34758087

  View details for PubMedCentralID PMC8804881

• Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization. BMC medicine Gormley, M., Dudding, T., Kachuri, L., Burrows, K., Chong, A. H., Martin, R. M., Thomas, S. J., Tyrrell, J., Ness, A. R., Brennan, P., Munafò, M. R., Pring, M., Boccia, S., Olshan, A. F., Diergaarde, B., Hung, R. J., Liu, G., Tajara, E. H., Severino, P., Toporcov, T. N., Lacko, M., Waterboer, T., Brenner, N., Smith, G. D., Vincent, E. E., Richmond, R. C. 2022; 20 (1): 40

  Abstract

  Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR).Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment.In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76).Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.

  View details for DOI 10.1186/s12916-022-02233-3

  View details for PubMedID 35094705

  View details for PubMedCentralID PMC8802428

• Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment. HGG advances Jiang, Y., Meyers, T. J., Emeka, A. A., Cooley, L. F., Cooper, P. R., Lancki, N., Helenowski, I., Kachuri, L., Lin, D. W., Stanford, J. L., Newcomb, L. F., Kolb, S., Finelli, A., Fleshner, N. E., Komisarenko, M., Eastham, J. A., Ehdaie, B., Benfante, N., Logothetis, C. J., Gregg, J. R., Perez, C. A., Garza, S., Kim, J., Marks, L. S., Delfin, M., Barsa, D., Vesprini, D., Klotz, L. H., Loblaw, A., Mamedov, A., Goldenberg, S. L., Higano, C. S., Spillane, M., Wu, E., Carter, H. B., Pavlovich, C. P., Mamawala, M., Landis, T., Carroll, P. R., Chan, J. M., Cooperberg, M. R., Cowan, J. E., Morgan, T. M., Siddiqui, J., Martin, R., Klein, E. A., Brittain, K., Gotwald, P., Barocas, D. A., Dallmer, J. R., Gordetsky, J. B., Steele, P., Kundu, S. D., Stockdale, J., Roobol, M. J., Venderbos, L. D., Sanda, M. G., Arnold, R., Patil, D., Evans, C. P., Dall'Era, M. A., Vij, A., Costello, A. J., Chow, K., Corcoran, N. M., Rais-Bahrami, S., Phares, C., Scherr, D. S., Flynn, T., Karnes, R. J., Koch, M., Dhondt, C. R., Nelson, J. B., McBride, D., Cookson, M. S., Stratton, K. L., Farriester, S., Hemken, E., Stadler, W. M., Pera, T., Banionyte, D., Bianco, F. J., Lopez, I. H., Loeb, S., Taneja, S. S., Byrne, N., Amling, C. L., Martinez, A., Boileau, L., Gaylis, F. D., Petkewicz, J., Kirwen, N., Helfand, B. T., Xu, J., Scholtens, D. M., Catalona, W. J., Witte, J. S. 1800; 3 (1)

  Abstract

  Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9*10-7 and GAB2, p = 2.0*10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

  View details for DOI 10.1016/j.xhgg.2021.100070

  View details for PubMedID 34993496

• A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility. Cancer research Emami, N. C., Cavazos, T. B., Rashkin, S. R., Cario, C. L., Graff, R. E., Tai, C. G., Mefford, J. A., Kachuri, L., Wan, E., Wong, S., Aaronson, D., Presti, J., Habel, L. A., Shan, J., Ranatunga, D. K., Chao, C. R., Ghai, N. R., Jorgenson, E., Sakoda, L. C., Kvale, M. N., Kwok, P. Y., Schaefer, C., Risch, N., Hoffmann, T. J., Van Den Eeden, S. K., Witte, J. S. 2021; 81 (7): 1695-1703

  Abstract

  To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637.

  View details for DOI 10.1158/0008-5472.CAN-20-2635

  View details for PubMedID 33293427

  View details for PubMedCentralID PMC8137514

• Cross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts. Nature communications Graff, R. E., Cavazos, T. B., Thai, K. K., Kachuri, L., Rashkin, S. R., Hoffman, J. D., Alexeeff, S. E., Blatchins, M., Meyers, T. J., Leong, L., Tai, C. G., Emami, N. C., Corley, D. A., Kushi, L. H., Ziv, E., Van Den Eeden, S. K., Jorgenson, E., Hoffmann, T. J., Habel, L. A., Witte, J. S., Sakoda, L. C. 2021; 12 (1): 970

  Abstract

  Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.

  View details for DOI 10.1038/s41467-021-21288-z

  View details for PubMedID 33579919

  View details for PubMedCentralID PMC7880989

• Insecticide use and risk of non-Hodgkin lymphoma subtypes: A subset meta-analysis of the North American Pooled Project. International journal of cancer Kachuri, L., Beane Freeman, L. E., Spinelli, J. J., Blair, A., Pahwa, M., Koutros, S., Hoar Zahm, S., Cantor, K. P., Weisenburger, D. D., Pahwa, P., Dosman, J. A., McLaughlin, J. R., Demers, P. A., Harris, S. A. 2020; 147 (12): 3370-3383

  Abstract

  Insecticide use has been linked to increased risk of non-Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self-reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype-specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20-2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17-2.16: FL, SLL) and DDT (OR = 1.36, 1.06-1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (Ptrend = 1.7 × 10-4 ), chlordane (Ptrend = 1.0 × 10-3 ) and DDT (Ptrend = 4.2 × 10-3 ), however, the exposure-response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45-9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75-16.53; Ptrend = 3.6 × 10-3 ). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure.

  View details for DOI 10.1002/ijc.33164

  View details for PubMedID 32574374

  View details for PubMedCentralID PMC7689728

• The landscape of host genetic factors involved in immune response to common viral infections. Genome medicine Kachuri, L., Francis, S. S., Morrison, M. L., Wendt, G. A., Bosse, Y., Cavazos, T. B., Rashkin, S. R., Ziv, E., Witte, J. S. 2020; 12 (1): 93

  Abstract

  BACKGROUND: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities.METHODS: We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort.RESULTS: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRbeta1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P<5.0*10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P=5.0*10-15 (MCV), NTN5: P=1.1*10-9 (BKV), and P2RY13: P=1.1*10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions.CONCLUSIONS: Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.

  View details for DOI 10.1186/s13073-020-00790-x

  View details for PubMedID 33109261

• Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts. Nature communications Rashkin, S. R., Graff, R. E., Kachuri, L., Thai, K. K., Alexeeff, S. E., Blatchins, M. A., Cavazos, T. B., Corley, D. A., Emami, N. C., Hoffman, J. D., Jorgenson, E., Kushi, L. H., Meyers, T. J., Van Den Eeden, S. K., Ziv, E., Habel, L. A., Hoffmann, T. J., Sakoda, L. C., Witte, J. S. 2020; 11 (1): 4423

  Abstract

  Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

  View details for DOI 10.1038/s41467-020-18246-6

  View details for PubMedID 32887889

  View details for PubMedCentralID PMC7473862

• Pesticide use and risk of Hodgkin lymphoma: results from the North American Pooled Project (NAPP). Cancer causes & control : CCC Latifovic, L., Freeman, L. E., Spinelli, J. J., Pahwa, M., Kachuri, L., Blair, A., Cantor, K. P., Zahm, S. H., Weisenburger, D. D., McLaughlin, J. R., Dosman, J. A., Pahwa, P., Koutros, S., Demers, P. A., Harris, S. A. 2020; 31 (6): 583-599

  Abstract

  The purpose of this study was to investigate associations between pesticide exposures and risk of Hodgkin lymphoma (HL) using data from the North American Pooled Project (NAPP).Three population-based studies conducted in Kansas, Nebraska, and six Canadian provinces (HL = 507, Controls = 3886) were pooled to estimate odds ratios and 95% confidence intervals for single (never/ever) and multiple (0, 1, 2-4, ≥ 5) pesticides used, duration (years) and, for select pesticides, frequency (days/year) using adjusted logistic regression models. An age-stratified analysis (≤ 40/ > 40 years) was conducted when numbers were sufficient.In an analysis of 26 individual pesticides, ever use of terbufos was significantly associated with HL (OR: 2.53, 95% CI 1.04-6.17). In age-stratified analyses, associations were stronger among those ≤ 40 years of age. No significant associations were noted among those > 40 years old; however, HL cases ≤ 40 were three times more likely to report ever using dimethoate (OR: 3.76 95% CI 1.02-33.84) and almost twice as likely to have ever used malathion (OR: 1.86 95% CI 1.00-3.47). Those ≤ 40 years of age reporting use of 5 + organophosphate insecticides had triple the odds of HL (OR: 3.00 95% CI 1.28-7.03). Longer duration of use of 2,4-D, ≥ 6 vs. 0 years, was associated with elevated odds of HL (OR: 2.59 95% CI 1.34-4.97).In the NAPP, insecticide use may increase the risk of HL, but results are based on small numbers.

  View details for DOI 10.1007/s10552-020-01301-4

  View details for PubMedID 32314107

  View details for PubMedCentralID PMC7183499

• Silica and asbestos exposure at work and the risk of bladder cancer in Canadian men: a population-based case-control study. BMC cancer Latifovic, L., Villeneuve, P. J., Parent, M. É., Kachuri, L., Harris, S. A. 2020; 20 (1): 171

  Abstract

  Silica and asbestos are recognized lung carcinogens. However, their role in carcinogenesis at other organs is less clear. Clearance of inhaled silica particles and asbestos fibers from the lungs may lead to translocation to sites such as the bladder where they may initiate carcinogenesis. We used data from a Canadian population-based case-control study to evaluate the associations between these workplace exposures and bladder cancer.Data from a population-based case-control study were used to characterize associations between workplace exposure to silica and asbestos and bladder cancer among men. Bladder cancer cases (N = 658) and age-frequency matched controls (N = 1360) were recruited within the National Enhanced Cancer Surveillance System from eight Canadian provinces (1994-97). Exposure concentration, frequency and reliability for silica and asbestos were assigned to each job, based on lifetime occupational histories, using a combination of job-exposure profiles and expert review. Exposure was modeled as ever/never, highest attained concentration, duration (years), highest attained frequency (% worktime) and cumulative exposure. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated using adjusted logistic regression.A modest (approximately 20%) increase in bladder cancer risk was found for ever having been exposed to silica, highest attained concentration and frequency of exposure but this increase was not statistically significant. Relative to unexposed, the odds of bladder cancer were 1.41 (95%CI: 1.01-1.98) times higher among men exposed to silica at work for ≥27 years. For asbestos, relative to unexposed, an increased risk of bladder cancer was observed for those first exposed ≥20 years ago (OR:2.04, 95%CI:1.25-3.34), those with a frequency of exposure of 5-30% of worktime (OR:1.45, 95%CI:1.06-1.98), and for those with < 10 years of exposure at low concentrations (OR:1.75, 95%CI:1.10-2.77) and the lower tertile of cumulative exposure (OR:1.69, 95%CI:1.07-2.65). However, no clear exposure-response relationships emerged.Our results indicate a slight increase in risk of bladder cancer with exposure to silica and asbestos, suggesting that the effects of these agents are broader than currently recognized. The findings from this study inform evidence-based action to enhance cancer prevention efforts, particularly for workers in industries with regular exposure.

  View details for DOI 10.1186/s12885-020-6644-7

  View details for PubMedID 32126982

  View details for PubMedCentralID PMC7055116

• Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility. Nature communications Kachuri, L., Johansson, M., Rashkin, S. R., Graff, R. E., Bossé, Y., Manem, V., Caporaso, N. E., Landi, M. T., Christiani, D. C., Vineis, P., Liu, G., Scelo, G., Zaridze, D., Shete, S. S., Albanes, D., Aldrich, M. C., Tardón, A., Rennert, G., Chen, C., Goodman, G. E., Doherty, J. A., Bickeböller, H., Field, J. K., Davies, M. P., Dawn Teare, M., Kiemeney, L. A., Bojesen, S. E., Haugen, A., Zienolddiny, S., Lam, S., Le Marchand, L., Cheng, I., Schabath, M. B., Duell, E. J., Andrew, A. S., Manjer, J., Lazarus, P., Arnold, S., McKay, J. D., Emami, N. C., Warkentin, M. T., Brhane, Y., Obeidat, M., Martin, R. M., Relton, C., Davey Smith, G., Haycock, P. C., Amos, C. I., Brennan, P., Witte, J. S., Hung, R. J. 2020; 11 (1): 27

  Abstract

  Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

  View details for DOI 10.1038/s41467-019-13855-2

  View details for PubMedID 31911640

  View details for PubMedCentralID PMC6946810

• Exposure to crystalline silica in Canadian workplaces and the risk of kidney cancer. Occupational and environmental medicine Peters, C. E., Bogaert, L., Latifovic, L., Kachuri, L., Harris, S. A., Parent, M. E., Villeneuve, P. J. 2019; 76 (9): 668-671

  Abstract

  The causes of kidney cancer are not well understood though occupational exposures are thought to play a role. Crystalline silica is a known human carcinogen, and despite previous links with kidney disease, there have been few studies investigating its association with kidney cancer. We addressed this research gap using a population-based case-control study of Canadian men.Questionnaire data were obtained from individuals with histologically confirmed kidney cancer, and population-based controls recruited from eight Canadian provinces (1994-1997). An industrial hygienist characterised participants' lifetime occupational exposure, and their confidence in the assessment (possibly, probably or definitely exposed) to silica on three dimensions (intensity, frequency and duration), and cumulative exposure was estimated. Logistic regression was used to estimate ORs and 95% CIs, adjusting for potential confounders.Nearly half of the 689 kidney cancer cases (49%) and 2369 controls (44%) had ever been occupationally exposed to crystalline silica. In a fully adjusted model, workers ever-exposed to silica had a slightly increased risk of kidney cancer relative to those who were unexposed (OR 1.10, 95% CI 0.92 to 1.32). Odds were modestly (and generally not statistically significantly) increased for models with duration of exposure and cumulative exposure, though exposure-response relationships were not evident.Our findings do not provide evidence that occupational exposure to crystalline silica increases risk of kidney cancer in men.

  View details for DOI 10.1136/oemed-2019-105870

  View details for PubMedID 31413189

• Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms. Nature communications Emami, N. C., Kachuri, L., Meyers, T. J., Das, R., Hoffman, J. D., Hoffmann, T. J., Hu, D., Shan, J., Feng, F. Y., Ziv, E., Van Den Eeden, S. K., Witte, J. S. 2019; 10 (1): 3107

  Abstract

  Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.

  View details for DOI 10.1038/s41467-019-10808-7

  View details for PubMedID 31308362

  View details for PubMedCentralID PMC6629701

• Investigation of Leukocyte Telomere Length and Genetic Variants in Chromosome 5p15.33 as Prognostic Markers in Lung Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Kachuri, L., Helby, J., Bojesen, S. E., Christiani, D. C., Su, L., Wu, X., Tardón, A., Fernández-Tardón, G., Field, J. K., Davies, M. P., Chen, C., Goodman, G. E., Shepherd, F. A., Leighl, N. B., Tsao, M. S., Brhane, Y., Brown, M. C., Boyd, K., Shepshelovich, D., Sun, L., Amos, C. I., Liu, G., Hung, R. J. 2019; 28 (7): 1228-1237

  Abstract

  Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus.Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases.Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3).Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration.This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

  View details for DOI 10.1158/1055-9965.EPI-18-1215

  View details for PubMedID 31263055

  View details for PubMedCentralID PMC6608599

• Non-Hodgkin lymphoma risk and organophosphate and carbamate insecticide use in the north American pooled project. Environment international Koutros, S., Harris, S. A., Spinelli, J. J., Blair, A., McLaughlin, J. R., Zahm, S. H., Kim, S., Albert, P. S., Kachuri, L., Pahwa, M., Cantor, K. P., Weisenburger, D. D., Pahwa, P., Pardo, L. A., Dosman, J. A., Demers, P. A., Beane Freeman, L. E. 2019; 127: 199-205

  Abstract

  Organophosphates and carbamates have been among the most commonly used insecticides, with both agricultural and residential uses. Previous studies have suggested associations of non-Hodgkin lymphoma (NHL) with some of these chemicals; however, many studies have been limited in their ability to evaluate associations with lymphoma subtypes. We evaluated the use of eleven organophosphate and two carbamate insecticides in association with NHL in the North American Pooled Project, which includes data from case-control studies in the United States and Canada (1690 cases/5131 controls). We used unconditional logistic regression adjusting for potential confounders, including use of other pesticides, to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between these chemicals and NHL overall, and NHL subtypes, i.e., follicular (FL), diffuse large B-cell (DLBCL), small lymphocytic lymphoma (SLL) and others. Ever use of malathion was associated with increased risk of NHL overall (OR = 1.43; 95% CI: 1.14-1.81) compared with never users. Categories using tertiles of duration (<4 yrs., 4-12 yrs., and >12 yrs) also showed a significant exposure-response for increasing years of use of malathion and risk of NHL (OR<4vsUnex = 1.33 (0.88, 2.03), OR4-12vsUnex = 1.42 (1.02, 1.96), OR>12vsUnex = 1.55 (1.05, 2.28, p-trend < 0.01)). In addition, malathion use was statistically significantly associated with FL (OR = 1.58; 95% CI: 1.11-2.27) and DLBCL (OR = 1.61; 95% CI: 1.16-2.22) while there were no apparent associations with SLL or other subtypes, the p-value for heterogeneity across subtypes, however, was not significant. These results support previous studies suggesting an association between insecticide use and NHL overall, and provide new information on associations with NHL subtypes.

  View details for DOI 10.1016/j.envint.2019.03.018

  View details for PubMedID 30928843

  View details for PubMedCentralID PMC6513687

• Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Zhu, Y., Wei, Y., Zhang, R., Dong, X., Shen, S., Zhao, Y., Bai, J., Albanes, D., Caporaso, N. E., Landi, M. T., Zhu, B., Chanock, S. J., Gu, F., Lam, S., Tsao, M. S., Shepherd, F. A., Tardon, A., Fernández-Somoano, A., Fernandez-Tardon, G., Chen, C., Barnett, M. J., Doherty, J., Bojesen, S. E., Johansson, M., Brennan, P., McKay, J. D., Carreras-Torres, R., Muley, T., Risch, A., Wichmann, H. E., Bickeboeller, H., Rosenberger, A., Rennert, G., Saliba, W., Arnold, S. M., Field, J. K., Davies, M. P., Marcus, M. W., Wu, X., Ye, Y., Le Marchand, L., Wilkens, L. R., Melander, O., Manjer, J., Brunnström, H., Hung, R. J., Liu, G., Brhane, Y., Kachuri, L., Andrew, A. S., Duell, E. J., Kiemeney, L. A., van der Heijden, E. H., Haugen, A., Zienolddiny, S., Skaug, V., Grankvist, K., Johansson, M., Woll, P. J., Cox, A., Taylor, F., Teare, D. M., Lazarus, P., Schabath, M. B., Aldrich, M. C., Houlston, R. S., McLaughlin, J., Stevens, V. L., Shen, H., Hu, Z., Dai, J., Amos, C. I., Han, Y., Zhu, D., Goodman, G. E., Chen, F., Christiani, D. C. 2019; 28 (5): 935-942

  Abstract

  Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear.We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk.Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings.Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention.These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.

  View details for DOI 10.1158/1055-9965.EPI-18-0356

  View details for PubMedID 30700444

• Personalized Prostate Cancer Screening Based on a Single Midlife Prostate-specific Antigen Measurement. European urology Graff, R. E., Kachuri, L., Witte, J. S. 2019; 75 (3): 408-409

  View details for DOI 10.1016/j.eururo.2018.09.019

  View details for PubMedID 30268658

• Occupational Exposure to Diesel and Gasoline Engine Exhausts and the Risk of Kidney Cancer in Canadian Men. Annals of work exposures and health Peters, C. E., Parent, M. É., Harris, S. A., Bogaert, L., Latifovic, L., Kachuri, L., Villeneuve, P. J. 2018; 62 (8): 978-989

  Abstract

  Kidney cancer is the fifth most common incident cancer in Canadian men. Diesel and gasoline exhausts are common workplace exposures that have been examined as risk factors for non-lung cancer sites, including the kidney, but limitations in exposure assessment methods have contributed to inconsistent findings. The objective of this study was to assess the relationship between occupational gasoline and diesel engine exhausts and the risk of kidney cancer in men.The National Enhanced Cancer Surveillance System (NECSS) is a Canadian population-based case-control study conducted in 1994-1997. Incident kidney cancer cases were identified using provincial registries, while the control series was identified through random-digit dialing, or provincial administrative databases. Self-reported questionnaires were used to obtain information on lifetime occupational history and cancer risk factors. Two hygienists, blinded to case status, coded occupational histories for diesel and gasoline exhaust exposures using concentration, frequency, duration, and reliability. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) separately by exhaust type. The separate and combined impacts of both engine exhausts were also examined. ORs were adjusted for age, province, body mass index, occupational secondhand smoke exposure, and education.Of the kidney cancer cases (n = 712), 372 (52%) had exposure to both exhausts at some point, and 984 (40%) of the controls (n = 2457) were ever exposed. Workers who had ever been exposed to engine exhausts were more likely to have kidney cancer than those who were never exposed (OR diesel = 1.23, 95% CI = 0.99-1.53; OR gasoline = 1.51, 95% CI = 1.23-1.86). Exposure to gasoline exhaust was consistently associated with kidney cancer in a dose-response manner (P value for trends in highest attained and cumulative exposure both <0.0001). Those men with high cumulative exposure to both gasoline and diesel exhaust had a 76% increased odds of kidney cancer (95% CI = 1.27-2.43).This study provides evidence that occupational gasoline, and to a lesser extent, diesel exhaust exposure may increase the risk of kidney cancer.

  View details for DOI 10.1093/annweh/wxy059

  View details for PubMedID 30059990

  View details for PubMedCentralID PMC6188530

• Workplace exposure to asbestos and the risk of kidney cancer in Canadian men. Canadian journal of public health = Revue canadienne de sante publique Peters, C. E., Parent, M. É., Harris, S. A., Kachuri, L., Latifovic, L., Bogaert, L., Villeneuve, P. J. 2018; 109 (4): 464-472

  Abstract

  Previous studies considered the role of occupational causes in kidney cancer but were limited by small sample sizes and imprecise exposure assessment. This study examined the relationship between occupational exposure to asbestos and the risk of kidney cancer across a range of jobs in a large, population-based case-control study in Canada.Data were from the case-control component of the National Enhanced Cancer Surveillance System, a study conducted between 1994 and 1997 in eight Canadian provinces. Male kidney cancer cases, histologically confirmed, and controls completed questionnaires on socio-demographics, anthropometry, diet, smoking, secondhand smoke exposure, and physical activity. Occupational histories were also collected, including each job held for at least 1 year since the age of 18. Occupational hygienists, blinded to case status, assigned exposure to asbestos, considering intensity, frequency, and probability of exposure (each 3-point scales). Logistic regression was used to estimate the odds of kidney cancer in exposed participants (defined using three metrics) compared to those without asbestos exposure.There were 712 cases and 2454 controls in these analyses. Ever-exposure to asbestos was associated with 20% increased odds of kidney cancer compared to unexposed workers (OR 1.2, 95% confidence interval 1.0-1.4 when including possibly exposed workers). A small increase in risk was observed with cumulative exposure, while increasing intensity of exposure was related to increased odds of kidney cancer.This study found some evidence for an association between occupational exposure to asbestos and kidney cancer. Higher intensity of exposure to asbestos had the strongest relationship with kidney cancer risk.

  View details for DOI 10.17269/s41997-018-0095-9

  View details for PubMedID 30225576

  View details for PubMedCentralID PMC6182333

• Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers. International journal of epidemiology Kachuri, L., Saarela, O., Bojesen, S. E., Davey Smith, G., Liu, G., Landi, M. T., Caporaso, N. E., Christiani, D. C., Johansson, M., Panico, S., Overvad, K., Trichopoulou, A., Vineis, P., Scelo, G., Zaridze, D., Wu, X., Albanes, D., Diergaarde, B., Lagiou, P., Macfarlane, G. J., Aldrich, M. C., Tardón, A., Rennert, G., Olshan, A. F., Weissler, M. C., Chen, C., Goodman, G. E., Doherty, J. A., Ness, A. R., Bickeböller, H., Wichmann, H. E., Risch, A., Field, J. K., Teare, M. D., Kiemeney, L. A., van der Heijden, E. H., Carroll, J. C., Haugen, A., Zienolddiny, S., Skaug, V., Wünsch-Filho, V., Tajara, E. H., Ayoub Moysés, R., Daumas Nunes, F., Lam, S., Eluf-Neto, J., Lacko, M., Peters, W. H., Le Marchand, L., Duell, E. J., Andrew, A. S., Franceschi, S., Schabath, M. B., Manjer, J., Arnold, S., Lazarus, P., Mukeriya, A., Swiatkowska, B., Janout, V., Holcatova, I., Stojsic, J., Mates, D., Lissowska, J., Boccia, S., Lesseur, C., Zong, X., McKay, J. D., Brennan, P., Amos, C. I., Hung, R. J. 2018

  Abstract

  Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

  View details for DOI 10.1093/ije/dyy140

  View details for PubMedID 30059977

• Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nature genetics McKay, J. D., Hung, R. J., Han, Y., Zong, X., Carreras-Torres, R., Christiani, D. C., Caporaso, N. E., Johansson, M., Xiao, X., Li, Y., Byun, J., Dunning, A., Pooley, K. A., Qian, D. C., Ji, X., Liu, G., Timofeeva, M. N., Bojesen, S. E., Wu, X., Le Marchand, L., Albanes, D., Bickeböller, H., Aldrich, M. C., Bush, W. S., Tardon, A., Rennert, G., Teare, M. D., Field, J. K., Kiemeney, L. A., Lazarus, P., Haugen, A., Lam, S., Schabath, M. B., Andrew, A. S., Shen, H., Hong, Y. C., Yuan, J. M., Bertazzi, P. A., Pesatori, A. C., Ye, Y., Diao, N., Su, L., Zhang, R., Brhane, Y., Leighl, N., Johansen, J. S., Mellemgaard, A., Saliba, W., Haiman, C. A., Wilkens, L. R., Fernandez-Somoano, A., Fernandez-Tardon, G., van der Heijden, H. F., Kim, J. H., Dai, J., Hu, Z., Davies, M. P., Marcus, M. W., Brunnström, H., Manjer, J., Melander, O., Muller, D. C., Overvad, K., Trichopoulou, A., Tumino, R., Doherty, J. A., Barnett, M. P., Chen, C., Goodman, G. E., Cox, A., Taylor, F., Woll, P., Brüske, I., Wichmann, H. E., Manz, J., Muley, T. R., Risch, A., Rosenberger, A., Grankvist, K., Johansson, M., Shepherd, F. A., Tsao, M. S., Arnold, S. M., Haura, E. B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T. M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Zienolddiny, S., Duell, E. J., Butler, L. M., Koh, W. P., Gao, Y. T., Houlston, R. S., McLaughlin, J., Stevens, V. L., Joubert, P., Lamontagne, M., Nickle, D. C., Obeidat, M., Timens, W., Zhu, B., Song, L., Kachuri, L., Artigas, M. S., Tobin, M. D., Wain, L. V., Rafnar, T., Thorgeirsson, T. E., Reginsson, G. W., Stefansson, K., Hancock, D. B., Bierut, L. J., Spitz, M. R., Gaddis, N. C., Lutz, S. M., Gu, F., Johnson, E. O., Kamal, A., Pikielny, C., Zhu, D., Lindströem, S., Jiang, X., Tyndale, R. F., Chenevix-Trench, G., Beesley, J., Bossé, Y., Chanock, S., Brennan, P., Landi, M. T., Amos, C. I. 2017; 49 (7): 1126-1132

  Abstract

  Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  View details for DOI 10.1038/ng.3892

  View details for PubMedID 28604730

  View details for PubMedCentralID PMC5510465

• Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC). BMC cancer Kachuri, L., Harris, M. A., MacLeod, J. S., Tjepkema, M., Peters, P. A., Demers, P. A. 2017; 17 (1): 343

  Abstract

  Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. We present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers.Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. Self-reported occupations were coded using the Standard Occupational Classification (1991) system. Analyses were restricted to employed persons aged 25-74 years at baseline (N = 2,051,315), with follow-up until December 31, 2010. Hazard ratios (HR) and 95% confidence intervals (CI) were modeled using Cox proportional hazards for all workers in agricultural occupations (n = 70,570; 70.8% male), stratified by sex, and adjusted for age at cohort entry, province of residence, and highest level of education.A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers.Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.

  View details for DOI 10.1186/s12885-017-3346-x

  View details for PubMedID 28525996

  View details for PubMedCentralID PMC5437486

• Systematic Review of Genetic Variation in Chromosome 5p15.33 and Telomere Length as Predictive and Prognostic Biomarkers for Lung Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Kachuri, L., Latifovic, L., Liu, G., Hung, R. J. 2016; 25 (12): 1537-1549

  Abstract

  Lung cancer remains the leading cause of cancer mortality worldwide. Known histomolecular characteristics and genomic profiles provide limited insight into factors influencing patient outcomes. Telomere length (TL) is important for genomic integrity and has been a growing area of interest as agents targeting telomerase are being evaluated. Chromosome 5p15.33, an established cancer susceptibility locus, contains a telomerase-regulatory gene, TERT, and CLPTM1L, a gene associated with cisplatin-induced apoptosis. This review offers a summary of the clinical utility of 5p15.33 polymorphisms and TL. A total of 621 abstracts were screened, and 14 studies (7 for 5p15.33, 7 for TL) were reviewed. Endpoints included overall survival (OS), progression-free survival (PFS), therapy response, and toxicity. Of the 23 genetic variants identified, significant associations with OS and/or PFS were reported for rs401681 (CLPTM1L), rs4975616 (TERT-CLPTM1L), and rs2736109 (TERT). Both shorter and longer TL, in tumor and blood, was linked to OS and PFS. Overall, consistent evidence across multiple studies of 5p15.33 polymorphisms and TL was lacking. Despite the potential to become useful prognostic biomarkers in lung cancer, the limited number of reports and their methodologic limitations highlight the need for larger, carefully designed studies with clinically defined subpopulations and higher resolution genetic analyses. Cancer Epidemiol Biomarkers Prev; 25(12); 1537-49. ©2016 AACR.

  View details for DOI 10.1158/1055-9965.EPI-16-0200

  View details for PubMedID 27566420

• Pesticide exposures and the risk of multiple myeloma in men: An analysis of the North American Pooled Project. International journal of cancer Presutti, R., Harris, S. A., Kachuri, L., Spinelli, J. J., Pahwa, M., Blair, A., Zahm, S. H., Cantor, K. P., Weisenburger, D. D., Pahwa, P., McLaughlin, J. R., Dosman, J. A., Freeman, L. B. 2016; 139 (8): 1703-14

  Abstract

  Multiple myeloma (MM) has been consistently linked with agricultural activities, including farming and pesticide exposures. Three case-control studies in the United States and Canada were pooled to create the North American Pooled Project (NAPP) to investigate associations between pesticide use and haematological cancer risk. This analysis used data from 547 MM cases and 2700 controls. Pesticide use was evaluated as follows: ever/never use; duration of use (years); and cumulative lifetime-days (LD) (days/year handled × years of use). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, province/state of residence, use of proxy respondents and selected medical conditions. Increased MM risk was observed for ever use of carbaryl (OR = 2.02, 95% CI = 1.28-3.21), captan (OR = 1.98, 95% CI = 1.04-3.77) and DDT (OR = 1.44, 95% CI = 1.05-1.97). Using the Canadian subset of NAPP data, we observed a more than threefold increase in MM risk (OR = 3.18, 95% CI = 1.40-7.23) for ≤10 cumulative LD of carbaryl use. The association was attenuated but remained significant for >10 LD of carbaryl use (OR = 2.44; 95% CI = 1.05-5.64; ptrend  = 0.01). For captan, ≤17.5 LD of exposure was also associated with a more than threefold increase in risk (OR = 3.52, 95% CI = 1.32-9.34), but this association was attenuated in the highest exposure category of >17.5 LD (OR = 2.29, 95% CI = 0.81-6.43; ptrend  = 0.01). An increasing trend (ptrend  = 0.04) was observed for LD of DDT use (LD > 22; OR = 1.92, 95% CI = 0.95-3.88). In this large North American study of MM and pesticide use, we observed significant increases in MM risk for use of carbaryl, captan and DDT.

  View details for DOI 10.1002/ijc.30218

  View details for PubMedID 27261772

• Workplace exposure to diesel and gasoline engine exhausts and the risk of colorectal cancer in Canadian men. Environmental health : a global access science source Kachuri, L., Villeneuve, P. J., Parent, M. É., Johnson, K. C., Harris, S. A. 2016; 15: 4

  Abstract

  The International Agency for Research on Cancer (IARC) classified diesel exhaust as carcinogenic to humans (Group 1) and gasoline exhaust as a possible carcinogen (Group 2B) based studies of lung cancer, however the evidence for other sites is limited. We addressed this question by investigating exposure to diesel and gasoline emissions with respect to risk of colorectal cancer in men.We used data from a population-based case-control study with incident cases of colon (n = 931) and rectal (n = 840) cancer and 1360 controls from 7 Canadian provinces conducted in 1994-1997. Lifetime occupational history and information on other risk factors was collected. Occupational hygienists, blinded to case-control status, assigned exposures to each job for 3 dimensions: concentration, frequency, and reliability. Logistic regression was used to estimate odds ratios (OR) and their 95 % confidence intervals (CI), adjusted for age, province, use of proxy respondents, smoking, body-mass index, physical activity, intake of alcohol, processed meats, and occupational exposure to asbestos and aromatic amines.Among CRC cases, 638 (36 %) were exposed to diesel and 814 (46 %) were exposed to gasoline emissions. Relative to the unexposed, elevated risks were observed among subjects ever exposed to high concentration levels of diesel emissions for colorectal cancer (OR = 1.65, 95 % CI = 0.98-2.80) and rectal cancer (OR = 1.98, 95 % CI = 1.09-3.60), but not colon cancer. Prolonged (>10 years) exposure at high concentrations was also associated with high risks of rectal cancer (OR = 2.33 95 % CI = 0.94-5.78; p-trend = 0.02). No statistically significant associations were observed for gasoline emissions.Our findings suggest that sustained high-level exposure diesel emissions may increase the risk of rectal cancer.

  View details for DOI 10.1186/s12940-016-0088-1

  View details for PubMedID 26762540

  View details for PubMedCentralID PMC4712563

• Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci. Carcinogenesis Kachuri, L., Amos, C. I., McKay, J. D., Johansson, M., Vineis, P., Bueno-de-Mesquita, H. B., Boutron-Ruault, M. C., Johansson, M., Quirós, J. R., Sieri, S., Travis, R. C., Weiderpass, E., Le Marchand, L., Henderson, B. E., Wilkens, L., Goodman, G. E., Chen, C., Doherty, J. A., Christiani, D. C., Wei, Y., Su, L., Tworoger, S., Zhang, X., Kraft, P., Zaridze, D., Field, J. K., Marcus, M. W., Davies, M. P., Hyde, R., Caporaso, N. E., Landi, M. T., Severi, G., Giles, G. G., Liu, G., McLaughlin, J. R., Li, Y., Xiao, X., Fehringer, G., Zong, X., Denroche, R. E., Zuzarte, P. C., McPherson, J. D., Brennan, P., Hung, R. J. 2016; 37 (1): 96-105

  Abstract

  Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000×) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73×10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64×10(-6)), rs112290073 (OR = 1.85, P = 1.27×10(-5)), rs138895564 (OR = 2.16, P = 2.06×10(-5); among young cases, OR = 3.77, P = 8.41×10(-4)). In addition, we found that rs139852726 (P = 1.44×10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84×10(-7)) and lung cancer (P = 2.37×10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.

  View details for DOI 10.1093/carcin/bgv165

  View details for PubMedID 26590902

  View details for PubMedCentralID PMC4715236

• Bladder cancer and occupational exposure to diesel and gasoline engine emissions among Canadian men. Cancer medicine Latifovic, L., Villeneuve, P. J., Parent, M. É., Johnson, K. C., Kachuri, L., Harris, S. A. 2015; 4 (12): 1948-62

  Abstract

  The International Agency for Research on Cancer has classified diesel exhaust as a carcinogen based on lung cancer evidence; however, few studies have investigated the effect of engine emissions on bladder cancer. The purpose of this study was to investigate the association between occupational exposure to diesel and gasoline emissions and bladder cancer in men using data from the Canadian National Enhanced Cancer Surveillance System; a population-based case-control study. This analysis included 658 bladder cancer cases and 1360 controls with information on lifetime occupational histories and a large number of possible cancer risk factors. A job-exposure matrix for engine emissions was supplemented by expert review to assign values for each job across three dimensions of exposure: concentration, frequency, and reliability. Odds ratios (OR) and their corresponding 95% confidence intervals were estimated using logistic regression. Relative to unexposed, men ever exposed to high concentrations of diesel emissions were at an increased risk of bladder cancer (OR = 1.64, 0.87-3.08), but this result was not significant, and those with >10 years of exposure to diesel emissions at high concentrations had a greater than twofold increase in risk (OR = 2.45, 1.04-5.74). Increased risk of bladder cancer was also observed with >30% of work time exposed to gasoline engine emissions (OR = 1.59, 1.04-2.43) relative to the unexposed, but only among men that had never been exposed to diesel emissions. Taken together, our findings support the hypothesis that exposure to high concentrations of diesel engine emissions may increase the risk of bladder cancer.

  View details for DOI 10.1002/cam4.544

  View details for PubMedID 26511593

  View details for PubMedCentralID PMC5123782

• Authors' response. Chronic diseases and injuries in Canada De, P., Kachuri, L., Ellison, L. F., Semenciw, R. 2014; 34 (4): 271

  View details for PubMedID 25408188

• Occupational exposure to crystalline silica and the risk of lung cancer in Canadian men. International journal of cancer Kachuri, L., Villeneuve, P. J., Parent, M. É., Johnson, K. C., Harris, S. A. 2014; 135 (1): 138-48

  Abstract

  Crystalline silica is a recognized carcinogen, but the association with lung cancer at lower levels of exposure has not been well characterized. This study investigated the relationship between occupational silica exposure and lung cancer and the combined effects of cigarette smoking and silica exposure on lung cancer risk. A population-based case-control study was conducted in eight Canadian provinces between 1994 and 1997. Self-reported questionnaires were used to obtain a lifetime occupational history and information on other risk factors. Occupational hygienists assigned silica exposures to each job based on concentration, frequency and reliability. Data from 1681 incident lung cancer cases and 2053 controls were analyzed using logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (CI). Models included adjustments for cigarette smoking, lifetime residential second-hand smoke and occupational exposure to diesel and gasoline engine emissions. Relative to the unexposed, increasing duration of silica exposure at any concentration was associated with a significant trend in lung cancer risk (OR ≥ 30 years: 1.67, 1.21-2.24; ptrend  = 0.002). The highest tertile of cumulative silica exposure was associated with lung cancer (OR = 1.81, 1.34-2.42; ptrend  = 0.004) relative to the lowest. Men exposed to silica for ≥30 years with ≥40 cigarette pack-years had the highest risk relative to those unexposed with <10 pack-years (OR = 42.53, 23.54-76.83). The joint relationship with smoking was consistent with a multiplicative model. Our findings suggest that occupational exposure to silica is a risk factor for lung cancer, independently from active and passive smoking, as well as from exposure to other lung carcinogens.

  View details for DOI 10.1002/ijc.28629

  View details for PubMedID 24272527

• Multiple pesticide exposures and the risk of multiple myeloma in Canadian men. International journal of cancer Kachuri, L., Demers, P. A., Blair, A., Spinelli, J. J., Pahwa, M., McLaughlin, J. R., Pahwa, P., Dosman, J. A., Harris, S. A. 2013; 133 (8): 1846-58

  Abstract

  Multiple myeloma (MM) has been linked to certain agricultural exposures, including pesticides. This analysis aimed to investigate the association between lifetime use of multiple pesticides and MM risk using two exposure metrics: number of pesticides used and days per year of pesticide use. A frequency-matched, population-based case-control study was conducted among men in six Canadian provinces between 1991 and 1994. Data from 342 MM cases and 1,357 controls were analyzed using logistic regression to calculate odds ratios (OR) and 95% confidence intervals. Pesticides were grouped by type, chemical class and carcinogenic potential, using a composite carcinogenic probability score. Selected individual pesticides were also examined. Regression models were adjusted for age, province of residence, use of proxy respondents, smoking and selected medical history variables. The overall pattern of results was complex. Positive trends in risk were observed for fungicides (ptrend=0.04) and pesticides classified as probably carcinogenic or higher (ptrend=0.03). Excess risks of MM were observed among men who reported using at least one carbamate pesticide (OR=1.94, 1.16-3.25), one phenoxy herbicide (OR=1.56, 1.09-2.25) and ≥3 organochlorines (OR=2.21, 1.05-4.66). Significantly higher odds of MM were seen for exposure to carbaryl (OR=2.71, 1.47-5.00) and captan (OR=2.96, 1.40-6.24). Use of mecoprop for >2 days per year was also significantly associated with MM (OR=2.15, 1.03-4.48). Focusing on multiple pesticide exposures is important because this more accurately reflects how exposures occur in occupational settings. Significant associations observed for certain chemical classes and individual pesticides suggest that these may be MM risk factors.

  View details for DOI 10.1002/ijc.28191

  View details for PubMedID 23564249

• Cancer incidence, mortality and survival trends in Canada, 1970-2007. Chronic diseases and injuries in Canada Kachuri, L., De, P., Ellison, L. F., Semenciw, R. 2013; 33 (2): 69-80

  Abstract

  Monitoring cancer trends can help evaluate progress in cancer control while reinforcing prevention activities. This analysis examines long-term trends for selected cancers in Canada using data from national databases.Annual changes in trends for age-standardized incidence and mortality rates between 1970 and 2007 were examined by sex for 1) all cancers combined, 2) the four most common cancers (prostate, breast, lung, colorectal) and 3) cancers that demonstrate the most recent notable changes in trend. Five-year relative survival for 1992-2007 was also calculated.Incidence rates for all primary cancer cases combined increased 0.9% per year in males and 0.8% per year in females over the study period, with varying degrees of increase for melanoma, thyroid, liver, prostate, kidney, colorectal, lung, breast, and bladder cancers and decrease for larynx, oral, stomach and cervical cancers. Mortality rates were characterized by significant declines for all cancers combined and for most cancers examined except for melanoma and female lung cancer. The largest improvements in cancer survival were for prostate, liver, colorectal and kidney cancers. While the overall trends in mortality rates and survival point to notable successes in cancer control, the increasing trend in incidence rates for some cancers emphasize the need for continued efforts in prevention.

  View details for PubMedID 23470172