title: Mismatch repair polymorphisms and the risk of colorectal cancer.
abstract: 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.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Platz
authors.forename: M Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Lucy W
authors.initials: LW
authors.lastname: Thuita
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Hoffman
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Helzlsouer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D053843:DNA Mismatch Repair; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1