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 colorectal carcinomas and is inherited in a dominant fashion. Two different forms can be distinguished. Type I is restricted to colorectal cancers, whereas type II patients acquire acolorectal, endometrial, gastric, small intestinal and transitional carcinomas of the upper urinary tract. Germline mutations in the human mismatch repair genes (hMSH2, hMSH6, hMLH1, hPMS2) account for the majority of hereditary non-polyposis colorectal carcinoma. As a result of the mismatch repair deficiency, replication errors are not repaired, resulting in a mutator phenotype. Simple repetitive sequences (microsatellites) are especially prone to replication errors and analysis of their stability combined with immunohistochemical analysis of mismatch repair protein expression provides a rapid diagnostic strategy. For patients either (1) fulfilling the Amsterdam criteria for HNPCC, (2) with synchronous or metachronous hereditary non-polyposis colorectal carcinoma-related tumors, (3) with hereditary non-polyposis colorectal carcinoma-related tumors before the age of 45 and/or (4) with right sided CRC and mucinous, solid, or cribriform growth patterns, screening for mismatch repair deficiencies should be performed. The identification of colorectal cancers displaying a mutator phenotype has implications for both treatment and prognosis.