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Type: Journal article
Title: DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer
Author: Worthley, D.
Whitehall, V.
Buttenshaw, R.
Irahara, N.
Greco, S.
Ramsnes, I.
Mallitt, K.
Le Leu, R.
Winter, J.
Hu, Y.
Ogino, S.
Young, G.
Leggett, B.
Citation: Oncogene, 2010; 29(11):1653-1662
Publisher: Nature Publishing Group
Issue Date: 2010
ISSN: 0950-9232
Statement of
DL Worthley, VLJ Whitehall, RL Buttenshaw, N Irahara, SA Greco, I Ramsnes, K-A Mallitt, RK Le Leu, J Winter, Y Hu, S Ogino, GP Young, and BA Leggett
Abstract: There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at ‘type A’ (ESR1, GATA5, HIC1, HPP1, SFRP1) and ‘type C’ markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. ‘Type A’ genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. ‘Type C’ methylation is more specific for neoplasia. The last five ‘type C’ markers comprise a CIMP panel. The mean ‘type A’ and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most ‘type A’ genes showed direct correlations between methylation and age (ESR1, ρ=0.66, P<0.0001), with higher methylation distally (ESR1, P<0.0001). On multivariate analysis, ‘type A’ methylation was inversely associated with colorectal adenomas (odds ratio=0.23, P<0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio=5.1, P=0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.
Keywords: DNA methylation; epigenetics; colorectal cancer; carcinogenesis
Rights: © 2010 Macmillan Publishers Limited
DOI: 10.1038/onc.2009.449
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