Mismatch repair polymorphisms and the risk of colorectal cancer

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case‐cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes ( MSH3 R940Q , MSH3 T1036A , MSH6 G39E and MLH1 I219V ) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR = 1.28, 95% CI: 0.94–1.74 and RR = 1.65, 95% CI: 1.01–2.70 for the AT and TT genotypes, respectively, with p trend = 0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall ( p trend = 0.07), it was associated with a significant increased risk of proximal colon cancer (RR = 1.69, 95% CI: 1.10–2.61 and RR = 2.68, 95% CI: 0.96–7.47 for the RQ and QQ genotypes, respectively with p trend = 0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer ( p interaction < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3 , may increase the risk of colorectal cancer, especially proximal colon cancer. © 2006 Wiley‐Liss, Inc.