Modifier gene polymorphisms and influence on disease expression in HNPCC

Abstract

Background Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal dominantly inherited predisposition to a variety of epithelial malignancies most notable colorectal and endometrial cancer. Unlike other genetic predispositions to colorectal cancer HNPCC does not present with a premalignant phenotype, which as such makes it difficult to predict when or if an affected person will present with disease. The genetic basis of HNPCC has been conclusively shown to be due to mutations in genes involved in DNA mismatch repair; hMLH1, hMSH2 hMSH6 and PMS2. Methods Several reports suggest that genetic modifiers of disease risk are capable of influencing the age of disease onset in HNPCC and it is likely that many of them have not yet been identified. Recently several genome-wide association studies have revealed a number of colorectal cancer susceptibility loci on chromosomes 10p14, 8q23.3, 8q24, 11q23 and 18q21. These loci are of particular importance as they are associated with an increased risk of colorectal cancer and may therefore act as modifiers of disease risk in individuals diagnosed with HNPCC. Materials and methods 373 Australian and 311 Polish HNPCC patients with a molecular diagnosis of HNPCC have been examined for nine polymorphisms in the five loci described above. All DNA samples were genotyped to determine the allele frequency in the nine polymorphisms investigated. A statistically evaluation of the exact nature of the effect on disease risk was assessed using the statistical software package SPSS Graduate Pack Version 12.0. Results In this study, hMLH1 mutation carriers harbouring the variant genotype for polymorphism rs3802842 were associated to development of colorectal cancer (CRC) at an earlier age than hMLH1 carriers harbouring the heterozygous or wild type genotype. This suggests that the particular polymorphism might act as a modifier for disease development in hMLH1 mutation carriers.