Journal
CANCER RESEARCH
Volume 69, Issue 1, Pages 282-291Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-3274
Keywords
-
Categories
Funding
- National Cancer Institute [CA077337, CA116676]
- National Science Foundation
- NIH [U54 RR 02438001]
- American Cancer Society [07-130-01-MGO]
- Frederick Gardner Cottrell Postdoctoral Fellowship
- Georgia Cancer Coalition Distinguished Cancer Scholar
- NATIONAL CANCER INSTITUTE [R01CA077337, P01CA116676, R01CA132065] Funding Source: NIH RePORTER
Ask authors/readers for more resources
Aberrant CpG island methylation is associated with transcriptional silencing of regulatory genes in human cancer. Although most CpG islands remain unmethylated, a subset accrues aberrant methylation in cancer via unknown mechanisms. Previously, we showed that CpG islands differ in their intrinsic propensity towards hypermethylation. We developed a classifier (PatMAn) based on the frequencies of seven DNA sequence patterns that discriminated methylation-prone (MP) and methylation-resistant (MR) CpG islands. Here, we report on the genome-wide application and direct testing of PatMAn in cancer. Although trained on data from a cell culture model of de novo methylation involving the overexpression of DNMT1, PatMAn accurately predicted CpG islands at increased risk of hypermethylation in cancer cell lines and primary tumors. Analysis of CpG islands predicted to be MP revealed a strong association with embryonic targets of polycomb-repressive complex 2 (PRC2), indicating that PatMAn predicts not only aberrant methylation, but also PRC2 binding. A second classifier (SUPER-PatMAn) that integrates the seven PatMAn DNA patterns with SUZ12 enriched regions as a marker of PRC2 occupancy showed improved performance (prediction accuracy, 81-88%). In addition to many non-PRC2 targets, SUPER-PatMAn identified a subset of PRC2 targets that were more likely to he hypermethylated in cancer. Genome-wide, CpG islands predicted to be MP were enriched in genes known to undergo hypermethylation in cancer, genes functioning in transcriptional regulation, and components of developmental pathways. These findings show that hypermethylation of certain gene loci is controlled in part by an underlying susceptibility influenced by both local sequence context and trans-acting factors. [Cancer Res 2009;69(1):282-91]
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available