The Association of the COMT V158M Polymorphism with Endometrial/Ovarian Cancer in HNPCC Families Adhering to the Amsterdam Criteria

Using Real Time PCR, the COMT V158M polymorphism was examined and its association with disease expression, age of diagnosis of cancer, mutation status and mutation type was assessed in the HNPCC MMR mutation positive and negative groups. This study showed that the V158M polymorphism had no association with disease risk in the HNPCC MMR mutation positive population. However, the polymorphism was significantly associated with endometrial/ovarian cancer risk in HNPCC MMR mutation negative patients (p = 0.002). The heterozygous (Val/Met) genotype was associated with an increased risk of developing endometrial/ovarian cancer whereas the homozygous mutant (Met/Met) showed a decreased risk. The results suggest heterosis, where there is an apparent greater effect of the heterozygous state in this dichotomous trait. In conclusion, this study shows that the COMT V158M polymorphism alters the risk of developing endometrial/ovarian cancer in patients that adhere to the Amsterdam HNPCC criteria but do not have a DNA mismatch repair gene mutation.Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant inherited disorder associated with a familial predisposition to colorectal cancer (CRC) and endometrial cancer (EC). It is characterised by early age of disease (CRC) onset, neoplastic lesions, microsatellite instability (MSI) and an increased incidence of extracolonic cancers [1]. Familial colorectal cancer syndromes, HNPCC and familial adenomatous polyposis (FAP), account for around 3% of all colorectal cancer cases; however, approximately 20% show familial inheritance of which there is no known genetic cause [2]. Mutations of the genes involved in the mismatch repair pathway, hMLH1 and hMSH2, account for a large proportion of patients that fit the HNPCC clinical criteria [1,3]. Approximately 80% of men and 40% of women that have germline mutations in MMR genes develop CRC [1,4] and 25-50% and 8-12% of women develop endometrial cancer and ovarian cancer, respec