首页|CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

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Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'(1,2). However, the existence of CIMP has been challenged(3,4). To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1. We propose a robust new marker panel to classify CIMP+ tumors.

DNA METHYLATIONCOLON-CANCERTRANSFORMATIONEPIGENETICSPROFILESCELLSFOS

Weisenberger DJ、D Siegmund K、Campan M、Young J、Long TI、Faasse MA、Kang GH、Widschwendter M、Weener D、Buchanan D

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Univ So Calif, Dept Surg, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA

Univ So Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA

Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA

Queensland Inst Med Res, Mol Canc Epidemiol Lab, Herston, Qld 4006, Australia

Seoul Natl Univ Hosp, Dept Pathol, Seoul 110744, South Korea

Univ Coll London, Dept Gynaecol Oncol, Inst Womens Hlth, London WC1E 6DH, England

Royal Brisbane & Womens Hosp Res Fdn, Conjoint Gastroenterol Lab, Clin Res Ctr, Herston, Qld 4006, Australia

McGill Univ, Dept Pathol, Montreal, PQ H3A 2B4, Canada

Mayo Clin & Mayo Fdn, Dept Lab Med, Rochester, MN 55905 USA

Mayo Clin & Mayo Fdn, Dept Pathol, Rochester, MN 55905 USA

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2006

Nature Genetics

Nature Genetics

SCI
ISSN：1061-4036
年,卷(期)：2006.38(7)