Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer

Recent characterization of the molecular genetic basis of hereditary nonpol yposis colorectal cancer provides an important opportunity for identificati on of individuals and their families with germline mutations in mismatch re pair genes. Cancer family history criteria that accurately define hereditar y colorectal cancer are necessary for cost-effective testing for germline m utations in mismatch repair genes. The present report describes the results of analysis of 33 colorectal cancer cases/families that satisfy our modifi ed family history criteria (Mount Sinai criteria) for colorectal cancer. Fo urteen of these families met the more stringent Amsterdam criteria. Germlin e MSH2 and MLH1 mutations were identified by the reverse transcription-poly merase chain reaction and the protein truncation test, and confirmed by seq uencing. Microsatellite instability analysis was performed on available tum ors from affected patients. MSH2 or MLH1 mutations were detected in 8 of 14 Amsterdam criteria families and in 5 of the remaining 19 cases/families th at only satisfied the Mount Sinai criteria. Three of the latter families ha d features of the Muir-Torre syndrome. A high level of microsatellite insta bility (MSI-H) was detected in almost all (16/18) colorectal cancers from i ndividuals with MSH2 and MLH1 mutations, and infrequently (1/21) in colorec tal cancer specimens from cases without detectable mutations. Families with germline MSH2 and MLH1 mutations tended to have individuals affected at yo unger ages and with multiple tumors. The Amsterdam criteria are useful, but not sufficient, for detecting hereditary colorectal cancer families with g ermline MSH2 and MLH1 mutations, since a proportion of cases and families w ith mutations in mismatch repair genes will be missed. Further development of cancer family history criteria are needed, using unbiased prospectively collected cases, to define more accurately those who will benefit from MSH2 and MLH1 mutation analysis.