Journal
MODERN PATHOLOGY
Volume 27, Issue 1, Pages 145-155Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/modpathol.2013.104
Keywords
colon polyps; colorectal cancer; CpG island methylator phenotype; epigenetics
Categories
Funding
- National Cancer Institute, NIH [CA078609, ES00002, 5 P42 ES05947, RR018787, R25CA134286, LM009012]
- National Institute of Environmental Health Sciences, NIH
- National Library of Medicine, NIH
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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 x 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.
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