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

Nature Genetics volume 41, pages 178–186 (2009)Cite this article

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.

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Acknowledgements

We thank B. Volgelstein (Johns Hopkins University School of Medicine) for providing colon tumors and matched normal mucosa samples. Postmortem brain, liver and spleen tissue was donated by The Stanley Medical Research Institute collection courtesy of M.B. Knable, E.F. Torrey and R.H. Yolken, whom we also thank for making available gene expression data for the brain and the liver tissue. We thank B. Carvalho for help with statistical software and C. Crainiceanu for advice with statistical methods. This work was supported by US National Institutes of Health grants P50HG003233 (A.P.F.), R37CA54358 (A.P.F.) and 5R01RR021967 (R.A.I.).

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Author notes

  1. Rafael A Irizarry, Christine Ladd-Acosta and Andrew P Feinberg: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA
    Rafael A Irizarry
  2. Center for Epigenetics, Institute for Basic Biomedical Sciences, Baltimore, 21205, Maryland, USA
    Rafael A Irizarry, Christine Ladd-Acosta, Bo Wen, Carolina Montano, Patrick Onyango, Hengmi Cui, Kevin Gabo, Michael Rongione, Hong Ji, James B Potash, Sarven Sabunciyan & Andrew P Feinberg
  3. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA
    Christine Ladd-Acosta, Bo Wen, Carolina Montano, Patrick Onyango, Hengmi Cui, Kevin Gabo, Michael Rongione, Hong Ji & Andrew P Feinberg
  4. Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA
    Zhijin Wu
  5. Stanley Laboratory of Brain Research, Uniformed Services University of Health Sciences, Bethesda, 20892, Maryland, USA
    Maree Webster
  6. Departments of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA
    James B Potash
  7. Pediatrics, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA
    Sarven Sabunciyan

Authors

  1. Rafael A Irizarry
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  2. Christine Ladd-Acosta
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  3. Bo Wen
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  4. Zhijin Wu
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  5. Carolina Montano
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  6. Patrick Onyango
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  7. Hengmi Cui
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  8. Kevin Gabo
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  9. Michael Rongione
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  10. Maree Webster
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  11. Hong Ji
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  12. James B Potash
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  13. Sarven Sabunciyan
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  14. Andrew P Feinberg
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Contributions

R.A.I. and A.P.F. designed the study and interpreted the results; R.A.I. designed new CHARM arrays and statistical methods with Z.W.; C.L.-A. performed bisulfite pyrosequencing, real-time quantitative PCR and sample preparation with C.M., K.G., M.R. and H.J.; B.W. and S.S. performed CHARM assays with sample preparation from M.W. and advice from J.B.P.; P.O. and H.C. performed functional assays; A.P.F. supervised the laboratory experiments and wrote the paper with R.A.I. and C.L.-A.

Corresponding authors

Correspondence toRafael A Irizarry or Andrew P Feinberg.

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Irizarry, R., Ladd-Acosta, C., Wen, B. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores.Nat Genet 41, 178–186 (2009). https://doi.org/10.1038/ng.298

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