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Introduction: Previous research has demonstrated increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide use and 324 single nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white pesticide applicators in the Agricultural Health Study, a prospective cohort of pesticide applicators in Iowa and North Carolina. Methods: We used likelihood ratio tests from logistic regression models to determine P-values for interactions between three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score and SNPs (assuming a dominant model). We employed the False Discovery Rate (FDR) method to adjust for multiple comparisons. Results: Of the seventeen interactions that met FDR Conclusions: While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B51.

Toll-like receptor 4 (TLR4) is located on the surface of macrophages and is important for the immune response to several pathogens. Chronic inflammation has been implicated in the pathogenesis of prostate cancer (PCa), and genetic polymorphisms of the innate immune gene TLR4 have been related to the risk of PCa. Six studies have explored the association between TLR4 polymorphisms and the risk of PCa. Five studies mainly included men of European ancestry. We conducted a systematic review of all genetic association studies that evaluated the relationship between TLR4 genotypes and aggressive PCa risk. We found the rs11536889 variant was significantly associated with an increased risk of aggressive PCa under a dominant genetic model [odds ratio (OR) = 1.20, 95% CI = 1.05-1.37]. However, rs1927914, rs2149356, or rs10759932 polymorphisms were not associated with the risk of PCa under any inheritance mode. In conclusion, this study found that the polymorphism TLR4 rs11536889 was significantly associated with the risk of aggressive PCa. Additional large-scale genetic association studies are needed to confirm these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1895. doi:10.1158/1538-7445.AM2011-1895

We identified and replicated specific combinations of three and four genetic variants that enhance bladder cancer risk in 5049 cases and 5452 controls. Different combinations were relevant in never, former and current smokers. The highest OR was obtained in never smokers (OR = 2.59)., Little is known whether genetic variants identified in genome-wide association studies interact to increase bladder cancer risk. Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case–control series (Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), 1501 cases, 1565 controls). In an independent case–control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered. The strongest four-variant combination was obtained in never smokers. The combination of rs1014971[AA] near apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) and chromobox homolog 6 (CBX6), solute carrier family 1s4 (urea transporter), member 1 (Kidd blood group) (SLC14A1) exon single nucleotide polymorphism (SNP) rs1058396[AG, GG], UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A) intron SNP rs11892031[AA] and rs8102137[CC, CT] near cyclin E1 (CCNE1) resulted in an unadjusted odds ratio (OR) of 2.59 (95% CI = 1.93–3.47; P = 1.87 × 10−10), while the individual variant ORs ranged only between 1.11 and 1.30. The combination replicated in the New England and Spanish Bladder Cancer Studies (ORunadjusted = 1.60, 95% CI = 1.10–2.33; P = 0.013). The four-variant combination is relatively frequent, with 25% in never smoking cases and 11% in never smoking controls (total study group: 19% cases, 14% controls). In conclusion, we show that four high-risk variants can statistically interact to confer increased bladder cancer risk particularly in never smokers.