The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores.
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.
Irizarry
Rafael A
RA
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.|Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ladd-Acosta
Christine
C
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Wen
Bo
B
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Wu
Zhijin
Z
Center for Statistical Sciences, Brown University, Providence, RI.
Montano
Carolina
C
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Onyango
Patrick
P
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cui
Hengmi
H
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Gabo
Kevin
K
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Rongione
Michael
M
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Webster
Maree
M
Stanley Laboratory of Brain Research, Uniform Services University of Health Sciences, Bethesda, MD 20892, USA.
Ji
Hong
H
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Potash
James
J
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sabunciyan
Sarven
S
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Feinberg
Andrew P
AP
Center for Epigenetics, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002874:Chromosome Mapping; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017124:Conserved Sequence; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000502:physiology*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology; D015894:Genome, Human; D045325:HCT116 Cells; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000235:genetics*
D015254:DNA Modification Methylases