Common germline variation in mismatch repair genes and survival after a diagnosis of colorectal cancer

Abstract

The mismatch repair (MMR) genes are involved in the maintenance of genomic integrity. Recently, we showed that common variants in these genes are unlikely to contribute significantly to colorectal cancer risk. The aim of this study was to investigate the role of common variants in the mismatch repair pathway as prognostic markers in colorectal cancer patients. We genotyped 2,060 patients for 68 SNPs in 7 mismatch repair genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2), using a single nucleotide polymorphism (SNP) tagging approach. Genotypes at the tag SNPs and multi-SNP haplotypes were tested for association with overall survival (OS) and disease specific survival (DSS) using a Cox regression model. Eight SNPs and 10 haplotypes were significant at a nominal p < 0.05 in the univariate analyses. Stepwise analysis showed that haplotype effects were mainly due to associated SNPs carried by these haplotypes. After adjustment for sex, age at diagnosis and stage when using overall survival and stage only when using disease specific survival, prognostic values were unattenuated. The most significant SNP associated with disease specific survival after adjustment was rs863221, located in MSH3 (HR: 0.59, 95% confidence interval (CI) 0.42-0.82, p-value: 0.001). In conclusion, we find some evidence that common variants in mismatch repair genes may contribute to survival of patients with colorectal cancer. © 2008 Wiley-Liss, Inc.