Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutchpedigree

Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genet ic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mis-match repair (MMR) genes MSH2 a nd MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP) , have also been shown to result in HNPCC. Preliminary data indicate that t he phenotype related to MSH6 mutations may differ from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterd am criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p<0.001) among the MSH6 mutation carriers in this family when compared with MSH2 and MLHI carriers (32% by the age of 80 v <greater than>80%). Endometrial cancer is a frequent manifestation among female carriers (six o ut of 13 malignant tumours). Transitional cell Abstract Hereditary non-poly posis colorectal cancer (HNPCC) is the most common genetic susceptibility s yndrome for colorectal Department of Pathology, Leiden University Medical C entre, The carcinoma of the urinary tract is relatively common in both male female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 5 5 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistoc hemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred con tributes to the establishment of genotype-phenotype correlations in HNPCC o wing to mutations in specific mismatch repair genes.