Molecular screening for hereditary nonpolyposis colorectal cancer: A prospective, population-based study

Purpose : Germline mutations in mismatch repair genes predispose to heredit ary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinica l investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland fou nd an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a hi gh-incidence area for colon cancer. Patients and Methods: Through the data of the local CRC registry, we prospe ctively collected all cases of CRC from January 1, 1996, through December 3 1, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the inciden t cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleoticle markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. Results: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases diffe red significantly from microsatellite-stable (MSS) cases for their proximal location (P < .01), high mucinous component (P < .01), and poor differenti ation (P = .002). Of MSI cases studied (n = 12), only one with a family his tory compatible with HNPCC had a germline mutation (in MSH2). Five other pa tients with a family history of HNPCC (two with MSI and three with MSS tumo rs) did not show germline mutations. Conclusion: We conclude that the incidence of molecularly confirmed HNPCC ( one [0.3%] of 336) in a high-incidence area for CRC is lower than in previo us biomolecular and clinical estimates. (C) 2001 by American Society of Cli nical Oncology.