Honors & Awards
Scholar in Training Award (AACR WICR), American Association for Cancer Research (2016)
Gordon Cressy Student Leadership Award, University of Toronto (2017)
Charles J. Epstein Trainee Award for Excellence in Human Genetics Research, American Society of Human Genetics (2019)
Scholar in Training Award (AACR MEG), American Association for Cancer Research (2020)
Boards, Advisory Committees, Professional Organizations
Scientific Program Committee, International Genetic Epidemiology Society (2022 - Present)
Postdoc, University of California San Francisco (2022)
PhD, Dalla Lana School of Public Health, University of Toronto (2018)
MPH, Dalla Lana School of Public Health, University of Toronto (2012)
BSc, McGill University (2010)
Genetically adjusted PSA levels for prostate cancer screening.
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.
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
2021; 108 (10): 1823-1835
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.
2020; 11 (1): 6084
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
Principles and methods for transferring polygenic risk scores across global populations.
Nature reviews. Genetics
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 2023
Development and testing of a polygenic risk score for breast cancer aggressiveness.
NPJ precision oncology
2023; 7 (1): 42
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.
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 2023
Inverted genomic regions between reference genome builds in humans impact imputation accuracy and decrease the power of association testing.
2023; 4 (1): 100159
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.
2022; 20 (1): 332
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.
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
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
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 2022; 24 (2): 182-183
Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.
2022; 20 (1): 40
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.
1800; 3 (1)
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.
2021; 81 (7): 1695-1703
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.
2021; 12 (1): 970
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
2020; 147 (12): 3370-3383
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.
2020; 12 (1): 93
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.
2020; 11 (1): 4423
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
2020; 31 (6): 583-599
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.
2020; 20 (1): 171
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.
2020; 11 (1): 27
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
2019; 76 (9): 668-671
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.
2019; 10 (1): 3107
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
2019; 28 (7): 1228-1237
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.
2019; 127: 199-205
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
2019; 28 (5): 935-942
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 2019; 75 (3): 408-409
Occupational Exposure to Diesel and Gasoline Engine Exhausts and the Risk of Kidney Cancer in Canadian Men.
Annals of work exposures and health
2018; 62 (8): 978-989
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
2018; 109 (4): 464-472
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
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.
2017; 49 (7): 1126-1132
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).
2017; 17 (1): 343
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
2016; 25 (12): 1537-1549
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
2016; 139 (8): 1703-14
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
2016; 15: 4
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.
2016; 37 (1): 96-105
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.
2015; 4 (12): 1948-62
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
Chronic diseases and injuries in Canada
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
2014; 135 (1): 138-48
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
2013; 133 (8): 1846-58
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
2013; 33 (2): 69-80
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