CANCER RISK IN FAMILIES WITH HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER DIAGNOSED BY MUTATION ANALYSIS

Background & Aims: Hereditary nonpolyposis colorectal cancer is charac terized by early-onset colorectal cancer and the occurrence of various other cancers, The recent isolation of four mismatch repair genes res ponsible for hereditary nonpolyposis colorectal cancer allows for the identification of carriers within affected families. The purpose of th is study was to assess the age-specific cancer risk in a large series of gene carriers, Methods: Thirty-four families were studied by mutati on analysis. In 19 of these families, pathogenic mutations were found at hMSH2 or hMLH1. Of 382 relatives, 124 had a mutation in hMLH1 and 8 6 in hMSH2, Results: The lifetime risk of colorectal cancer was the sa me in both groups of gene carriers (80%), The risk of endometrial canc er was greater in hMSH2 gene carriers compared with hMLH1 gene carrier s (61% vs. 42%), but the difference was not statistically significant. A very high relative risk of cancer of the small bowel (relative risk of >100) was observed in carriers of either gene, Only the carriers o f hMSH2 mutations had a significantly increased relative risk of cance r of the urinary tract (kidney and ureter) (relative risk of 75.3), st omach (relative risk of 19.3), and ovaries (relative risk of 8.0). Con clusions: This study provides estimates of cancer risk that may contri bute to the appropriate management of gene carriers within families wi th hereditary nonpolyposisis colorectal cancer.