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Molecular Characterization of MSI-H Colorectal Cancer by MLHI Promoter Methylation, Immunohistochemistry, and Mismatch Repair Germline Mutation Screening

Departments of ¹ Preventive Medicine and ² Surgery and Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California; Departments of ³ Laboratory Medicine and Pathology and ⁴ Medical Genetics, Mayo Clinic, Rochester, Minnesota; ⁵ Familial Cancer Laboratory, Queensland Institute of Medical Research, Queensland, Australia; ⁶ Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia; ⁷ Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire; ⁸ Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii; ⁹ Cancer Care Ontario and ¹⁰ Department of Pathology and Lab Medicine, Mount Sinai Hospital, Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Ontario, Canada; and ¹¹ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Peter W. Laird, Departments of Surgery and of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, NOR 6418, Los Angeles, CA 90033-9176. Phone: 323-865-0650; Fax: 323-865-0158. E-mail: plaird{at}usc.edu

Microsatellite instability (MSI) occurs in 10% to 20% of colorectal cancers (CRC) and has been attributed to both MLH1 promoter hypermethylation and germline mutation in the mismatch repair (MMR) genes. We present results from a large population- and clinic-based study of MLH1 methylation, immunohistochemistry, and MMR germline mutations that enabled us to (a) estimate the prevalence of MMR germline mutations and MLH1 methylation among MSI-H cases and help us understand if all MSI-H CRC is explained by these mechanisms and (b) estimate the associations between MLH1 methylation and sex, age, and tumor location within the colon. MLH1 methylation was measured in 1,061 population-based and 172 clinic-based cases of CRC. Overall, we observed MLH1 methylation in 60% of population-based MSI-H cases and in 13% of clinic-based MSI-H cases. Within the population-based cases with MMR mutation screening and conclusive immunohistochemistry results, we identified a molecular event in MMR in 91% of MSI-H cases: 54% had MLH1 methylation, 14% had a germline mutation in a MMR gene, and 23% had immunohistochemistry evidence for loss of a MMR protein. We observed a striking age difference, with the prevalence of a MMR germline mutation more than 4-fold lower and the prevalence of MLH1 methylation more than 4-fold higher in cases diagnosed after the age of 50 years than in cases diagnosed before that age. We also determined that female sex is an independent predictor of MLH1 methylation within the MSI-H subgroup. These results reinforce the importance of distinguishing between the underlying causes of MSI in studies of etiology and prognosis. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3208–15)

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