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

Abstract：

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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

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

doi

10.1053/j.gastro.2014.04.039

subject

Has Abstract

pub_date

2014-08-01 00:00:00

pages

418-29.e8

issue

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(14)00595-2

journal_volume

147

pub_type

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