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Molecular Screening for Hereditary Nonpolyposis Colorectal Cancer: A Prospective, Population-Based Study

From the Departments of Internal Medicine and Pathology, University of Modena, Modena; Division of Pathology, Ospedale di Carpi, Carpi; Division of Experimental Oncology I, Centro Riferimento Oncologico, Aviano; and Department of Medical Genetics, Catholic University of Rome, Rome, Italy; Institute for Medical Radiobiology, University of Zurich, Switzerland; Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland; and Division of Human Cancer Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH.

Address reprint requests to Antonio Percesepe, MD, PhD, Department of Internal Medicine, University of Modena, Via del Pozzo 71, 41100 Modena, Italy; email: percesepe.antonio{at}unimo.it

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found 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 high-incidence area for colon cancer.

PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide 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 differed significantly from microsatellite-stable (MSS) cases for their proximal location (P < .01), high mucinous component (P < .01), and poor differentiation (P = .002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) 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 previous biomolecular and clinical estimates.

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