Author:
Xu Yaomin,Hu Bo,Choi Ae-Jin,Gopalan Banu,Lee Byron H.,Kalady Matthew F.,Church James M.,Ting Angela H.
Abstract
A subset of colorectal cancers was postulated to have the CpG island methylator phenotype (CIMP), a higher propensity for CpG island DNA methylation. The validity of CIMP, its molecular basis, and its prognostic value remain highly controversial. Using MBD-isolated genome sequencing, we mapped and compared genome-wide DNA methylation profiles of normal, non-CIMP, and CIMP colon specimens. Multidimensional scaling analysis revealed that each specimen could be clearly classified as normal, non-CIMP, and CIMP, thus signifying that these three groups have distinctly different global methylation patterns. We discovered 3780 sites in various genomic contexts that were hypermethylated in both non-CIMP and CIMP colon cancers when compared with normal colon. An additional 2026 sites were found to be hypermethylated in CIMP tumors only; and importantly, 80% of these sites were located in CpG islands. These data demonstrate on a genome-wide level that the additional hypermethylation seen in CIMP tumors occurs almost exclusively at CpG islands and support definitively that these tumors were appropriately named. When these sites were examined more closely, we found that 25% were adjacent to sites that were also hypermethylated in non-CIMP tumors. Thus, CIMP is also characterized by more extensive methylation of sites that are already prone to be hypermethylated in colon cancer. These observations indicate that CIMP tumors have specific defects in controlling both DNA methylation seeding and spreading and serve as an important first step in delineating molecular mechanisms that control these processes.
Publisher
Cold Spring Harbor Laboratory
Subject
Genetics(clinical),Genetics
Reference57 articles.
1. Colorectal Cancer "Methylator Phenotype": Fact or Artifact?
2. Conserved mechanism of PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: Identification of SII as a new fusion partner gene;Cancer Res,1999
3. Fitting a mixture model by expectation maximization to discover motifs in biopolymers;Proc Int Conf Intell Syst Mol Biol,1994
4. Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a Population-Based Series of 582 Cases
5. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene
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