Originally published as JCO Early Release 10.1200/JCO.2005.04.671 on August 22 2005

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Use of Molecular Tumor Characteristics to Prioritize Mismatch Repair Gene Testing in Early-Onset Colorectal Cancer

From the Genetic Epidemiology Laboratory, Department of Pathology; Centre for Molecular, Environmental, Genetic, and Analytical Epidemiology, The University of Melbourne, Parkville; Genetic Technologies Limited, Kew; Peter MacCallum Cancer Centre, East Melbourne; The Australian Red Cross Blood Service, Melbourne; Department of Anatomical Pathology, Western Hospital, Footscray; Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne; Cancer Epidemiology Centre, The Cancer Council, Carlton, Victoria; ACCFR Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Queensland, Australia; and Department of Pathology, McGill University, Quebec, Canada

Address reprint requests to John L. Hopper, PhD, Centre for Molecular, Environmental, Genetic, and Analytical Epidemiology, Department of Public Health, The University of Melbourne, 723 Swanston St, Carlton, Victoria 3053, Australia; e-mail: j.hopper{at}unimelb.edu.au

PURPOSE: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis.

METHODS: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins.

RESULTS: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%.

CONCLUSIONS: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation–carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

Supported by grants from the National Health and Medical Research Council (Australia) and the Victorian Health Promotion Foundation.

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

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