title: Distinct patterns of DNA methylation in conventional adenomas involving the right and left colon.
abstract: Recent studies have shown two distinct non-CIMP methylation clusters in colorectal cancer, raising the possibility that DNA methylation, involving non-CIMP genes, may play a role in the conventional adenoma-carcinoma pathway. A total of 135 adenomas (65 left colon and 70 right colon) were profiled for epigenome-wide DNA methylation using the Illumina HumanMethylation450 BeadChip. A principal components analysis was performed to examine the association between variability in DNA methylation and adenoma location. Linear regression and linear mixed effects models were used to identify locus-specific differential DNA methylation in adenomas of right and left colon. A significant association was present between the first principal component and adenoma location (P=0.007), even after adjustment for subject age and gender (P=0.009). A total of 168 CpG sites were differentially methylated between right- and left-colon adenomas and these loci demonstrated enrichment of homeobox genes (P=3.0 × 10(-12)). None of the 168 probes were associated with CIMP genes. Among CpG loci with the largest difference in methylation between right- and left-colon adenomas, probes associated with PRAC (prostate cancer susceptibility candidate) gene showed hypermethylation in right-colon adenomas whereas those associated with CDX2 (caudal type homeobox transcription factor 2) showed hypermethylation in left-colon adenomas. A subgroup of left-colon adenomas enriched for current smokers (OR=6.1, P=0.004) exhibited a methylation profile similar to right-colon adenomas. In summary, our results indicate distinct patterns of DNA methylation, independent of CIMP genes, in adenomas of the right and left colon.
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA.
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsongalis
authors.affiliation: Department of Gastroenterology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Lynn F
authors.initials: LF
authors.lastname: Butterly
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Goodrich
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA.
authors.forename: Corina
authors.initials: C
authors.lastname: Lesseur
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.affiliation: 1] Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA [2] Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.affiliation: 1] Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA [2] Department of Genetics, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA.
authors.forename: Angeline S
authors.initials: AS
authors.lastname: Andrew
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Srivastava
mesh_terms: D000236:Adenoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000071616:CDX2 Transcription Factor; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D009687:Nuclear Proteins / Q000235:genetics; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D025341:Principal Component Analysis; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C425926:PRAC1 protein, human