INCIDENCE OF HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER AND THE FEASIBILITY OF MOLECULAR SCREENING FOR THE DISEASE

Background Genetic disorders that predispose people to colorectal canc er include the polyposis syndromes and hereditary nonpolyposis colorec tal cancer. In contrast to the polyposis syndromes, hereditary nonpoly posis colorectal cancer lacks distinctive clinical features. However, a germ-line mutation of DNA mismatch-repair genes is a characteristic molecular feature of the disease. Since clinical screening of carriers of such mutations can help prevent cancer, it is important to devise strategies applicable to molecular screening for this disease. Methods We prospectively screened tumor specimens obtained from 509 consecuti ve patients with colorectal adenocarcinomas for DNA replication errors , which are characteristic of hereditary colorectal cancers. These rep lication errors were detected through microsatellite-marker analyses o f tumor DNA. DNA from normal tissue from the patients with replication errors was screened for germ-line mutations of the mismatch-repair ge nes MLH1 and MSH2. Results Among the 509 patients, 63 (12 percent) had replication errors. Specimens of normal tissue from 10 of these 63 pa tients had a germ-line mutation of MLH1 or MSH2. Of these 10 patients (2 per cent of the 509 patients), 9 had a first-degree relative with e ndometrial or colorectal cancer, 7 were under 50 years of age, and 4 h ad had colorectal or endometrial cancer previously. Conclusions In thi s series of patients with colorectal-cancer in Finland, at least 2 per cent had hereditary nonpolyposis colorectal cancer. We recommend testi ng for replication errors in all patients with colorectal cancer who m eet one or more of the following criteria: a family history of colorec tal or endometrial cancer, an age of less than 50 years, and a history of multiple colorectal or endometrial cancers. Patients found to have replication errors should undergo further analysis for germ-line muta tions in DNA mismatch-repair genes. (C) 1998, Massachusetts Medical So ciety.