TY - JOUR
T1 - The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores
AU - Irizarry, Rafael A.
AU - Ladd-Acosta, Christine
AU - Wen, Bo
AU - Wu, Zhijin
AU - Montano, Carolina
AU - Onyango, Patrick
AU - Cui, Hengmi
AU - Gabo, Kevin
AU - Rongione, Michael
AU - Webster, Maree
AU - Ji, Hong
AU - Potash, James B.
AU - Sabunciyan, Sarven
AU - Feinberg, Andrew P.
N1 - Funding Information:
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.).
PY - 2009/2
Y1 - 2009/2
N2 - 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.
AB - 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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U2 - 10.1038/ng.298
DO - 10.1038/ng.298
M3 - Article
C2 - 19151715
AN - SCOPUS:59149084538
SN - 1061-4036
VL - 41
SP - 178
EP - 186
JO - Nature genetics
JF - Nature genetics
IS - 2
ER -