Genetic variations in XRCC2 and XRCC3 are not associated with endometrial cancer risk.

Introduction Endometrial cancer is a component of hereditary nonpolyposis colorectal carcinoma, primarily the consequence of mutations in genes involved in mismatch repair (MMR; MSH2, MLH1, PMS1, and PMS2). In addition to the repair of DNA replication errors, MMR genes have been implicated in homologous recombination repair (HRR) in yeast and in mammalian cells (1, 2). The involvement of the MMR genes in the DNA HRR pathway implies that defects in the HRR pathway may contribute to the development of hereditary nonpolyposis colorectal carcinoma tumorigenesis. Recently, Mohindra et al. (3) reported that human tumor cell lines (colon, uterine, ovarian, and endometrial) deficient in MMR also had defects in HRR induced by DNA double-strand breaks, and these tumor cell lines were hypersensitive to thymidine, which was not due to MMR deficiency or deoxynucleoside triphosphate pool imbalance. A XRCC2 frameshift mutation identified in the MMR-deficient uterine tumor cell line SKUT-1 conferred hypersensitivity to thymidine or mitomycin C in a MMR-proficient line, suggesting that HRR defects may lead to the thymidine sensitivity of MMR-deficient tumor cell lines (3). These findings additionally support the hypothesis that HRR deficiency may confer susceptibility to hereditary nonpolyposis colorectal carcinoma tumorigenesis. XRCC2 and XRCC3, as two RAD51 paralogues, facilitate the formation of RAD51 foci formation in HRR. We assessed whether candidate polymorphisms in XRCC2 and XRCC3 genes in HRR pathway are associated with endometrial cancer risk in a nested case-control study within the Nurses’ Health Study.