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

  1. Jenny N. Poynter1,
  2. Kimberly D. Siegmund1,
  3. Daniel J. Weisenberger2,
  4. Tiffany I. Long2,
  5. Stephen N. Thibodeau3,
  6. Noralane Lindor4,
  7. Joanne Young5,
  8. Mark A. Jenkins6,
  9. John L. Hopper6,
  10. John A. Baron7,
  11. Dan Buchanan5,
  12. Graham Casey1,
  13. A. Joan Levine1,
  14. Loïc Le Marchand8,
  15. Steven Gallinger9,
  16. Bharati Bapat10,
  17. John D. Potter11,
  18. Polly A. Newcomb11,
  19. Robert W. Haile1,
  20. Peter W. Laird2 and
  21. for the Colon Cancer Family Registry Investigators
  1. Departments of 1Preventive Medicine and 2Surgery and Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California; Departments of 3Laboratory Medicine and Pathology and 4Medical Genetics, Mayo Clinic, Rochester, Minnesota; 5Familial Cancer Laboratory, Queensland Institute of Medical Research, Queensland, Australia; 6Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia; 7Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire; 8Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii; 9Cancer Care Ontario and 10Department of Pathology and Lab Medicine, Mount Sinai Hospital, Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Ontario, Canada; and 11Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
  1. 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

Abstract

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)

Footnotes

  • Grant support: This work was supported by the National Cancer Institute, NIH, under RFA CA-95-011 and through cooperative agreements with the Australasian Colorectal Cancer Family Registry (U01 CA097735), the University of Southern California Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), the Seattle Colorectal Cancer Family Registry (U01 CA074794), and the University of Hawaii Colorectal Cancer Family Registry (U01 CA074806) as well as National Cancer Institute T32 CA009142 (J.N. Poynter).

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

    • Accepted September 3, 2008.
    • Received June 3, 2008.
    • Revision received August 21, 2008.
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  1. doi: 10.1158/1055-9965.EPI-08-0512 Cancer Epidemiology, Biomarkers & Prevention November 1, 2008 17, 3208
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