Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors.

PURPOSE: Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information. EXPERIMENTAL DESIGN: We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors. RESULTS: Non-silent KDM6A mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater ERCC2-Signature mutations compared with former (P = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; P = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations (P = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; P = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with ERCC2-Signature mutations and APOBEC-Signature13 mutations among current (P trend = 0.005) and former smokers (P = 0.0004), respectively. CONCLUSIONS: These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.

Bladder cancer risk associated with family history of cancer.

Twin studies suggest a familial aggregation of bladder cancer, but elements of this increased familial risk of bladder cancer are not well understood. To characterize familial risk of bladder cancer, we examined the relationship between family history of bladder and other types of cancer among first-degree relatives and risk of bladder cancer in 1193 bladder cancer cases and 1418 controls in a large population-based case-control study. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between family history of bladder cancer (defined as at least one first-degree family member with bladder cancer or a cancer of any other site). We also evaluated cancer aggregation of specific sites in family members. Participants with a first-degree relative with bladder cancer had nearly double the risk of bladder cancer (OR = 1.8, 95% CI 1.2-2.9) as those without a family history of bladder cancer. Risk was increased for having a sibling with bladder cancer (OR = 2.6, 95% CI 1.3-5.3) compared to no siblings with cancer. Bladder cancer risk was elevated when participants reported a first-degree relative with a history of female genital cancer (OR = 1.5, 95% CI 1.1-2.1), melanoma (OR = 1.9, 95% CI 1.02-3.6), and tobacco-associated cancer (OR = 1.3, 95% CI 1.06-1.6). These findings add to evidence of a familial predisposition to bladder cancer. Clarification of the aggregation of bladder cancer in families and with other cancer sites will be of interest as many loci and common polymorphisms related to bladder cancer have yet to be identified in large genomic studies.

Pesticide exposure and risk of aggressive prostate cancer among private pesticide applicators.

BACKGROUND: Prostate cancer (PCa) is one of the most commonly diagnosed cancers among men in developed countries; however, little is known about modifiable risk factors. Some studies have implicated organochlorine and organophosphate insecticides as risk factors (particularly the organodithioate class) and risk of clinically significant PCa subtypes. However, few studies have evaluated other pesticides. We used data from the Agricultural Health Study, a large prospective cohort of pesticide applicators in North Carolina and Iowa, to extend our previous work and evaluate 39 additional pesticides and aggressive PCa. METHODS: We used Cox proportional hazards models, with age as the time scale, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ever use of individual pesticides and 883 cases of aggressive PCa (distant stage, poorly differentiated grade, Gleason score ≥ 7, or fatal prostate cancer) diagnosed between 1993 and 2015. All models adjusted for birth year, state, family history of PCa, race, and smoking status. We conducted exposure-response analyses for pesticides with reported lifetime years of use. RESULTS: There was an increased aggressive PCa risk among ever users of the organodithioate insecticide dimethoate (n = 54 exposed cases, HR = 1.37, 95% CI = 1.04, 1.80) compared to never users. We observed an inverse association between aggressive PCa and the herbicide triclopyr (n = 35 exposed cases, HR = 0.68, 95% CI = 0.48, 0.95), with the strongest inverse association for those reporting durations of use above the median (≥ 4 years; n = 13 exposed cases, HR=0.44, 95% CI=0.26, 0.77). CONCLUSION: Few additional pesticides were associated with prostate cancer risk after evaluation of extended data from this large cohort of private pesticide applicators.

Non-Hodgkin lymphoma risk and organophosphate and carbamate insecticide use in the north American pooled project.

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.