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Gastroenterology. 2014 Aug;147(2):418-29.e8. doi: 10.1053/j.gastro.2014.04.039. Epub 2014 Apr 30.

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

Author information

1
Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Electronic address: luoyx25@mail.sysu.edu.cn.
2
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Research and Development Service, VA Puget Sound Health Care System, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
4
Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China.
5
Department of Pathology, Case Medical Center, Case Comprehensive Cancer Center and Case Western Reserve University, Cleveland, Ohio.
6
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
7
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), University of Heidelberg, Heidelberg, Germany GDR.
8
Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, Ohio.
9
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
10
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington. Electronic address: wgrady@fhcrc.org.

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.

KEYWORDS:

Colon Cancer; Epigenetic Modifications; Gene Regulation; Progression

PMID:
24793120
PMCID:
PMC4107146
DOI:
10.1053/j.gastro.2014.04.039
[Indexed for MEDLINE]
Free PMC Article

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