The increased risk of endometrial cancer associated with unopposed exogenous estrogens and high levels of endogenous estrogens (as are present in obesity) has been hypothesized to result, at least in part, via two possible mechanisms: 1) increased cellular proliferation, and 2) through the production of estrogen metabolites, which can result in DNA damage by directly binding to DNA and forming bulky DNA adducts, and/or indirectly through the production of reactive oxygen species. Thus, interindividual variation in the ability to repair such damage might influence a woman's risk of endometrial cancer. To test this hypothesis, we examined whether the presence of the minor alleles in 64 tag SNPs in the nucleotide excision repair genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, XPA, and XPC was associated with risk of endometrial cancer in a population-based case-control study in Washington State, with 726 cases ages 50-74 years diagnosed between 1994-2005, and 736 controls frequency-matched to the cases by age. The analyses were restricted to non-Hispanic white women. Most of the genotypes that we investigated were not associated with endometrial cancer risk. However, the presence of the rs4150386 C allele (ERCC5), the rs3730865 C allele (LIG1), and the rs3731127 T allele (XPC) was associated with risk, with respective age-adjusted per-allele odds ratios (ORs) and 95% confidence intervals (CIs) of 0.68 (0.53-0.87), 1.50 (1.05-2.14) and 1.52 (1.10-2.10). The association between rs4150386 and endometrial cancer risk was considerably stronger among obese women (body mass index (BMI)≥30 kg/m2: per-C-allele OR=0.40, 95% CI 0.24-0.65) compared to women with BMI<30 kg/m2 (per-C-allele OR=0.86, 95% CI 0.64-1.14), while the association with rs3730865 was stronger among lighter versus heavier weight women (per-C-allele ORs and 95% CIs were: 1.69, 95% CI 1.12-2.56 for BMI<30 kg/m2, and 1.15, 95% CI 0.55-2.42 for BMI≥30 kg/m2). The association with rs3731127 did not vary by BMI, and the altered risk associated with the minor alleles of the three SNPs did not vary by use of long-term unopposed estrogens. Because of the multiple redundancies in DNA repair pathways and the large number of possible associations examined, there is the potential for false positive findings, both overall and in BMI subgroups. Any conclusions regarding the influence of NER genotypes on risk of endometrial cancer await the results of additional studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-415.