Background: Genetic disorders that predispose people to colorectal cancer include the polyposis syndromes and hereditary nonpolyposis colorectal cancer. In contrast to the polyposis syndromes, hereditary nonpolyposis 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 consecutive patients with colorectal adenocarcinomas for DNA replication errors, which are characteristic of hereditary colorectal cancers. These replication errors were detected through microsatellite-marker analyses of tumor DNA. DNA from normal tissue from the patients with replication errors was screened for germ-line mutations of the mismatch-repair genes MLH1 and MSH2. Results: Among the 509 patients, 63 (12 percent) had replication errors. Specimens of normal tissue from 10 of these 63 patients had a germ-line mutation of MLH1 or MSH2. Of these 10 patients (2 percent of the 509 patients), 9 had a first-degree relative with endometrial or colorectal cancer, 7 were under 50 years of age, and 4 had had colorectal or endometrial cancer previously. Conclusions: In this series of patients with colorectal cancer in Finland, at least 2 percent had hereditary nonpolyposis colorectal cancer. We recommend testing for replication errors in all patients with colorectal cancer who meet one or more of the following criteria: a family history of colorectal 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 mutations in DNA mismatch-repair genes.
Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease / Aaltonen, Lauri A.; Salovaara, Reijo; Kristo, Paula; Canzian, Federico; Hemminki, Akseli; Peltomäki, Päivi; Chadwick, Robert B.; Kääriäinen, Helena; Eskelinen, Matti; Järvinen, Heikki; Mecklin, Jukka-Pekka; De La Chapelle, Albert; Percesepe, Antonio; Ahtola, Heikki; Härkönen, Niilo; Julkunen, Risto; Kangas, Eero; Ojala, Seppo; Tulikoura, Jukka; Valkamo, Erkki. - In: NEW ENGLAND JOURNAL OF MEDICINE. - ISSN 0028-4793. - 338:21(1998), pp. 1481-1487. [10.1056/NEJM199805213382101]
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