Nature Genetics 38, 787 - 793 (2006)
Published online: 25 June 2006; | doi:10.1038/ng1834
CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancerDaniel J Weisenberger1, 9, Kimberly D Siegmund2, 9, Mihaela Campan1, Joanne Young3, Tiffany I Long1, Mark A Faasse1, Gyeong Hoon Kang4, Martin Widschwendter5, Deborah Weener1, Daniel Buchanan3, Hoey Koh6, Lisa Simms6, Melissa Barker3, Barbara Leggett6, Joan Levine2, Myungjin Kim1, Amy J French7, Stephen N Thibodeau7, Jeremy Jass8, Robert Haile2 & Peter W Laird11
Departments of Surgery and of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
90089-9176, USA. 2
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
90089-9176, USA. 3
Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Herston, Queensland
4006, Australia. 4
Department of Pathology, Seoul National University Hospital, Seoul
110-744, Korea. 5
Institute for Women's Health, Department of Gynaecological Oncology, University College London, London
WC1E 6DH, UK. 6
Conjoint Gastroenterology Laboratory, Royal Brisbane & Women's Hospital Research Foundation, Clinical Research Centre, Herston, Queensland
4006, Australia. 7
Departments of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
55905, USA. 8
Department of Pathology, McGill University, Montreal
QC
H3A 2B4, Canada. 9
These authors contributed equally to this work.
Correspondence should be addressed to Peter W Laird plaird@usc.edu 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 challenged3,
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 BRAFmutation (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.
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