Analysis of the Association between CIMP and BRAF(V600E) in Colorectal Cancer by DNA Methylation Profiling

Hinoue, Toshinori, Weisenberger, Daniel J., Pan, Fei, Campan, Mihaela, Kim, Myungjin, Young, Joanne, Whitehall, Vicki L., Leggett, Barbara A. and Laird, Peter W. (2009) Analysis of the Association between CIMP and BRAF(V600E) in Colorectal Cancer by DNA Methylation Profiling. PLoS One, 4 12: . doi:10.1371/journal.pone.0008357

Author Hinoue, Toshinori
Weisenberger, Daniel J.
Pan, Fei
Campan, Mihaela
Kim, Myungjin
Young, Joanne
Whitehall, Vicki L.
Leggett, Barbara A.
Laird, Peter W.
Title Analysis of the Association between CIMP and BRAF(V600E) in Colorectal Cancer by DNA Methylation Profiling
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2009-12-21
Sub-type Article (original research)
DOI 10.1371/journal.pone.0008357
Open Access Status DOI
Volume 4
Issue 12
Total pages 12
Place of publication United States
Publisher Public Library of Science
Language eng
Subject 11 Medical and Health Sciences
Formatted abstract
A CpG island methylator phenotype (CIMP) is displayed by a distinct subset of colorectal cancers with a high frequency of DNA hypermethylation in a specific group of CpG islands. Recent studies have shown that an activating mutation of BRAF (BRAFV600E) is tightly associated with CIMP, raising the question of whether BRAFV600E plays a causal role in the development of CIMP or whether CIMP provides a favorable environment for the acquisition of BRAFV600E. We employed Illumina GoldenGate DNA methylation technology, which interrogates 1,505 CpG sites in 807 different genes, to further study this association. We first examined whether expression of BRAFV600E causes DNA hypermethylation by stably expressing BRAFV600E in the CIMP-negative, BRAF wild-type COLO 320DM colorectal cancer cell line. We determined 100 CIMP-associated CpG sites and examined changes in DNA methylation in eight stably transfected clones over multiple passages. We found that BRAFV600E is not sufficient to induce CIMP in our system. Secondly, considering the alternative possibility, we identified genes whose DNA hypermethylation was closely linked to BRAFV600E and CIMP in 235 primary colorectal tumors. Interestingly, genes that showed the most significant link include those that mediate various signaling pathways implicated in colorectal tumorigenesis, such as BMP3 and BMP6 (BMP signaling), EPHA3, KIT, and FLT1 (receptor tyrosine kinases) and SMO (Hedgehog signaling). Furthermore, we identified CIMP-dependent DNA hypermethylation of IGFBP7, which has been shown to mediate BRAFV600E-induced cellular senescence and apoptosis. Promoter DNA hypermethylation of IGFBP7 was associated with silencing of the gene. CIMP-specific inactivation of BRAFV600E-induced senescence and apoptosis pathways by IGFBP7 DNA hypermethylation might create a favorable context for the acquisition of BRAFV600E in CIMP+ colorectal cancer. Our data will be useful for future investigations toward understanding CIMP in colorectal cancer and gaining insights into the role of aberrant DNA hypermethylation in colorectal tumorigenesis.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Article number: e8357.

Document type: Journal Article
Sub-type: Article (original research)
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Created: Sun, 10 Jan 2010, 00:02:19 EST