The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores

Rafael A. Irizarry, Christine Ladd-Acosta, Bo Wen, Zhijin Wu, Carolina Montano, Patrick Onyango, Hengmi Cui, Kevin Gabo, Michael Rongione, Maree Webster, Hong Ji, James B. Potash, Sarven Sabunciyan, Andrew P. Feinberg

Research output: Contribution to journalArticle

Abstract

For the past 25 years, it has been known that alterations in DNA methylation (DNAm) occur in cancer, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands, but in sequences up to 2 kb distant, which we term 'CpG island shores'. CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a notable overlap (45-65%) of the locations of colon cancer-related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling that of noncolon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, consistent with the epigenetic progenitor model of cancer, which proposes that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.

Original languageEnglish (US)
Pages (from-to)178-186
Number of pages9
JournalNature genetics
Volume41
Issue number2
DOIs
StatePublished - Feb 1 2009

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores'. Together they form a unique fingerprint.

  • Cite this