A DNA hypermethylation module for the stem/progenitor cell signature of cancer
- Hariharan Easwaran1,7,
- Sarah E. Johnstone1,7,
- Leander Van Neste2,
- Joyce Ohm3,
- Tim Mosbruger1,
- Qiuju Wang1,
- Martin J. Aryee1,
- Patrick Joyce1,
- Nita Ahuja1,
- Dan Weisenberger4,
- Eric Collisson5,
- Jingchun Zhu6,
- Srinivasan Yegnasubramanian1,
- William Matsui1 and
- Stephen B. Baylin1,8
- 1The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Johns Hopkins Medical Institutions, Baltimore, Maryland 21117, USA;
- 2MDxHealth PharmacoDx BVBA, 9052 Ghent, Belgium;
- 3University of North Dakota, School of Medicine and Health Sciences, Grand Fork, North Dakota 58202, USA;
- 4University of Southern California, Los Angeles, California 90033-9601, USA;
- 5Division of Hematology/Oncology, University of California, San Francisco, California 94143, USA;
- 6Center for Biomolecular Science & Engineering, University of California, Santa Cruz, California 95064, USA
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↵7 These authors contributed equally to this work.
Abstract
Many DNA-hypermethylated cancer genes are occupied by the Polycomb (PcG) repressor complex in embryonic stem cells (ESCs). Their prevalence in the full spectrum of cancers, the exact context of chromatin involved, and their status in adult cell renewal systems are unknown. Using a genome-wide analysis, we demonstrate that ∼75% of hypermethylated genes are marked by PcG in the context of bivalent chromatin in both ESCs and adult stem/progenitor cells. A large number of these genes are key developmental regulators, and a subset, which we call the “DNA hypermethylation module,” comprises a portion of the PcG target genes that are down-regulated in cancer. Genes with bivalent chromatin have a low, poised gene transcription state that has been shown to maintain stemness and self-renewal in normal stem cells. However, when DNA-hypermethylated in tumors, we find that these genes are further repressed. We also show that the methylation status of these genes can cluster important subtypes of colon and breast cancers. By evaluating the subsets of genes that are methylated in different cancers with consideration of their chromatin status in ESCs, we provide evidence that DNA hypermethylation preferentially targets the subset of PcG genes that are developmental regulators, and this may contribute to the stem-like state of cancer. Additionally, the capacity for global methylation profiling to cluster tumors by phenotype may have important implications for further refining tumor behavior patterns that may ultimately aid therapeutic interventions.
Footnotes
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↵8 Corresponding author.
E-mail sbaylin{at}jhmi.edu.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.131169.111.
Freely available online through the Genome Research Open Access option.
- Received August 29, 2011.
- Accepted February 6, 2012.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
