title: The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores.
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.
authors.affiliation: 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.
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Irizarry
authors.affiliation: 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Ladd-Acosta
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Wen
authors.affiliation: Center for Statistical Sciences, Brown University, Providence, RI.
authors.forename: Zhijin
authors.initials: Z
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Carolina
authors.initials: C
authors.lastname: Montano
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Onyango
authors.affiliation: 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.
authors.forename: Hengmi
authors.initials: H
authors.lastname: Cui
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gabo
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Rongione
authors.affiliation: Stanley Laboratory of Brain Research, Uniform Services University of Health Sciences, Bethesda, MD 20892, USA.
authors.forename: Maree
authors.initials: M
authors.lastname: Webster
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: James
authors.initials: J
authors.lastname: Potash
authors.affiliation: 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.
authors.forename: Sarven
authors.initials: S
authors.lastname: Sabunciyan
authors.affiliation: 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.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feinberg
mesh_terms: 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*
chemical_list: D015254:DNA Modification Methylases