Molecular diagnostics of cancer predisposition: hereditary non-polyposis colorectal carcinoma and mismatch repair defects

Hereditary non-polyposis colorectal carcinoma accounts for 5-13% of all col orectal carcinomas and is inherited in a dominant fashion. Two different fo rms can be distinguished. Type I is restricted to colorectal cancers, where as type II patients acquire acolorectal, endometrial, gastric, small intest inal and transitional carcinomas of the upper urinary tract. Germline mutat ions in the human mismatch repair genes (hMSH2, hMSH6, hMLH1, hPMS2) accoun t for the majority of hereditary non-polyposis colorectal carcinoma. As a r esult of the mismatch repair deficiency, replication errors are not repaire d, resulting in a mutator phenotype. Simple repetitive sequences (microsate llites) are especially prone to replication errors and analysis of their st ability combined with immunohistochemical analysis of mismatch repair prote in expression provides a rapid diagnostic strategy. For patients either (1) fulfilling the Amsterdam criteria for HNPCC, (2) with synchronous or metac hronous hereditary non-polyposis colorectal carcinoma-related tumors, (3) w ith hereditary nonpolyposis colorectal carcinoma-related tumors before the age of 45 and/or (4) with right sided CRC and mucinous, solid, or cribrifor m growth patterns, screening for mismatch repair deficiencies should be per formed. The identification of colorectal cancers displaying a mutator pheno type has implications for both treatment and prognosis. (C) 1999 Elsevier S cience B.V. All rights reserved.