Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer.

Luo Y, Wong CJ, Kaz AM, Dzieciatkowski S, Carter KT, Morris SM, Wang J, Willis JE, Makar KW, Ulrich CM, Lutterbaugh JD, Shrubsole MJ, Zheng W, Markowitz SD, Grady WM
Gastroenterology. 2014 147 (2): 418-29.e8

PMID: 24793120 · PMCID: PMC4107146 · DOI:10.1053/j.gastro.2014.04.039

BACKGROUND & AIMS - Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation.

METHODS - We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays.

RESULTS - We found genome-wide alterations in DNA methylation in the nontumor colon mucosa and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation and low-frequency methylation. Within the high-frequency methylation adenoma class a subset of adenomas had mutant KRAS. Additionally, the high-frequency methylation adenoma class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, and the low-frequency methylation adenoma class had methylation signatures similar to that of nontumor colon tissue. The CpG sites that were differentially methylated in these signatures are located in intragenic and intergenic regions.

CONCLUSIONS - Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (23)

Adenoma Aged Case-Control Studies Cell Transformation, Neoplastic Cluster Analysis Colorectal Neoplasms CpG Islands Disease Progression DNA Methylation DNA Mutational Analysis Epigenesis, Genetic Gene Expression Profiling Gene Expression Regulation, Neoplastic Genetic Predisposition to Disease Genome-Wide Association Study Humans Middle Aged Mutation Oligonucleotide Array Sequence Analysis Phenotype Proto-Oncogene Proteins Proto-Oncogene Proteins p21(ras) ras Proteins

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