Linda Kachuri

Occupational exposure to crystalline silica and the risk of lung cancer in Canadian men.

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.

Fine-mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci

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.

Multiple pesticide exposures and the risk of multiple myeloma in Canadian men

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.

Pesticide exposures and the risk of multiple myeloma in men: An analysis of the North American Pooled Project.

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.

Systematic Review of Genetic Variation in Chromosome 5p15.33 and Telomere Length as Predictive and Prognostic Biomarkers for Lung Cancer

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.

Bladder cancer and occupational exposure to diesel and gasoline engine emissions among Canadian men.

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.

Occupational Exposure to Diesel and Gasoline Engine Exhausts and the Risk of Kidney Cancer in Canadian Men

Abstract Introduction 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. Methods 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. Results 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). Conclusions This study provides evidence that occupational gasoline, and to a lesser extent, diesel exhaust exposure may increase the risk of kidney cancer.

0286 Occupational exposure to gasoline and diesel exhausts and the risk of kidney cancer in canadian men

Objectives The objective of this study was to investigate whether occupational gasoline and/or diesel exhaust exposure contribute to kidney cancer risk. Methods The National Enhanced Cancer Surveillance System is a population-based case-control study conducted from 1994–1997 in Canada. Incident kidney cancer cases were identified using provincial registries, while the control series were identified through random digit dialling, or provincial datasets. Self-reported questionnaires obtained information on lifetime occupational history and cancer risk factors. Hygienists coded occupational histories for diesel and gasoline exhaust exposures using concentration, frequency, duration and reliability. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals separately by exhaust type. Models were adjusted for age, province, BMI, and cigarette smoking. Results Complete occupational data were available for 652 cases and 2368 controls. The majority of workers had been exposed to diesel (53%) or gasoline (55%) exhausts, respectively; most exposures were at low concentrations. Workers who had ever been exposed were significantly more likely to have kidney cancer than those who were never exposed (OR diesel: 1.4;1.1–1.6, OR gasoline: 1.7;1.4–2.1). When examining duration of exposure and tertiles of cumulative exposure, diesel and gasoline exposures were both linked to a significantly increased risk of kidney cancer (p<0.05), but no exposure-response pattern was evident. Exposure to gasoline exhaust showed stronger positive relationships with kidney cancer than diesel. Conclusions This study provides evidence that occupational gasoline and to a lesser extent, diesel exhaust exposure increases the risk of kidney cancer.

Abstract 2292: Lung function and lung cancer risk: a Mendelian randomization study of UK Biobank cohort and the International Lung Cancer Consortium

Background: Impaired lung function (LF) is strongly associated with increased lung cancer risk. However, since airflow obstruction is a diagnostic criterion for obstructive lung disease, and a consequence of tobacco smoking, isolating the causal relationship between LF and lung cancer has remained a challenge. Methods: We investigated 3 standardized (mean=0, standard deviation=1) LF metrics: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC. To evaluate the causal relevance of LF in lung cancer etiology we conducted: i) survival analyses in the UK Biobank cohort (UKB); and ii) Mendelian Randomization (MR) analyses using genetic instrumental variables (IVs) developed in UKB and tested using individual-level data from the OncoArray, a genome-wide array with in-depth coverage for common cancers. Results: 702 incident lung cancers were diagnosed in 484,194 UKB participants during follow-up. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for age, sex, smoking status, socioeconomic status, and assessment center. Adjustment for other smoking metrics yielded similar results. Lung cancer risk increased per 1 unit decrease in FEV1 (HR=1.80, 95% CI: 1.64-1.98, p=3.3×10-34), FVC (HR=1.45, 1.30-1.60, p=2.3×10-12), and FEV1/FVC (HR=1.39, 1.33-1.46, p=1.3×10-38). This pattern was observed for adenocarcinoma (n=300): FEV1 (HR=1.77, p=6.0×10-12), FVC (HR=1.48, p=1.4×10-5), FEV1/FVC (HR=1.34, p=8.3×10-11); and squamous cell carcinoma (n=166): FEV1 (HR=1.97, p=9.9×10-10), FVC (HR=1.60, p=1.0×10-4), FEV1/FVC (HR=1.38, p=5.9×10-8). Next, a genome-wide association study of 67,708 UKB participants and 12.6 million variants was carried out to develop genetic IVs for LF. Results were filtered to retain independent variants (R2 80% European ancestry) from 23 studies. Effect estimates were combined using maximum-likelihood MR models to estimate causal ORs. MR results indicate that genetic scores associated with improved airflow are unrelated to lung cancer risk: FEV1 (OR=1.00, 95% CI: 0.96-1.03, p=0.86), FVC (OR=1.00, 0.97-1.03, p=0.93) and FEV1/FVC (OR=1.00, 0.91-1.10, p=0.95). The null association observed for the genetic determinants of FEV1, FVC and FEV1/FVC was not modified by tumor histology or smoking status. Conclusions: LF is a robust predictor of lung cancer risk, however, our findings do not support the existence of causal pathways that are independent of obstructive lung disease or smoking. This apparent lack of a causal relationship should be interpreted with caution since pleiotropic effects of LF loci cannot be ruled out. Citation Format: Linda Kachuri, Mattias Johansson, Paul Brennan, Phillip Haycock, Geoffrey Liu, Maria Teresa Landi, David C. Christiani, Neil E. Caporaso, Xifeng Wu, Melinda C. Aldrich, Demetrius Albanes, Adonina Tardon, Gad Rennert, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, Heike Bickeboller, Dawn Teare, Lambertus A. Kiemeney, Stig E. Bojesen, John K. Field, Aage Haugen, Stephen Lam, Loic Le Marchand, Matthew B. Schabath, Angeline S. Andrew, Jonas Manjer, Philip Lazarus, Susanne M. Arnold, Valerie Gaborieau, Richard Martin, Caroline Relton, George Davey Smith, Christopher I. Amos, James D. McKay, Rayjean J. Hung. Lung function and lung cancer risk: a Mendelian randomization study of UK Biobank cohort and the International Lung Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2292. doi:10.1158/1538-7445.AM2017-2292

0295 Occupational exposure to crystalline silica and the risk of lung cancer in Canadian men

Objectives Crystalline silica is a recognised carcinogen, but the association with lung cancer at lower levels of exposure has not been well characterised. 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. Method A population-based case-control study was conducted in 8 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 analysed using logistic regression to estimate odds ratios (OR) and their 95% confidence intervals. Models included adjustments for cigarette smoking, lifetime residential second-hand smoke, and occupational exposure to diesel and gasoline engine emissions. Results 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. Conclusions 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.