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Immunohistochemistry Identifies Carriers of Mismatch Repair Gene Defects Causing Hereditary Nonpolyposis Colorectal Cancer

From the Section of Genetic Counselling, Department of Cancer Genetics, The Norwegian Radium Hospital; Department of Pathology, Ullevål University Hospital, Oslo; Department of Occupational and Environmental Medicine, Telemark Hospital, Skien; Telemark University College, Bø; Center of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

Address reprint requests to Pål Møller, Section of Genetic Counselling, Department of Cancer Genetics, The Norwegian Radium Hospital, N-0310 Oslo, Norway; e-mail: pal.moller{at}klinmed.uio.no

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by mutations in mismatch repair (MMR) genes. The aim of this study was to validate immunohistochemistry and family history as prescreening tools to predict germline mutations in MLH1, MSH2, and MSH6.

PATIENTS AND METHODS: Pedigrees from 250 families were extended, cancer diagnoses were verified, and families were classified according to the Amsterdam and the Bethesda criteria. Tumor specimens were examined with immunohistochemistry for the presence of MLH1, MSH2, and MSH6 proteins. Mutation analyses were performed in blood samples from the same patients.

RESULTS: Blood samples from affected index persons in 181 families and tumor specimens from 127 of the affected index persons were obtained. Thirty tumors lacked one or more gene products. Sensitivity of immunohistochemistry to detect mutation carriers was 100%, specificity was 82%, and positive predictive value was 85%. Sensitivities, specificities, and positive predictive values for the Amsterdam criteria were 82%, 8%, and 45%, respectively, and for the Bethesda criteria were 100%, 0%, and 48%, respectively. Distribution of mutations was MLH1 = 4, MSH2 = 11, and MSH6 = 4.

CONCLUSION: Wide clinical criteria to select HNPCC kindreds, followed by immunohistochemistry of tumor material from one affected person in each family, had high sensitivity and specificity to predict MMR mutations.

Supported by the Norwegian Cancer Society (grant No. E00078).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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