DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

D. L. Worthley, V. L J Whitehall, R. L. Buttenshaw, N. Irahara, S. A. Greco, I. Ramsnes, K. A. Mallitt, R. K. Le Leu, J. Winter, Y. Hu, S. Ogino, G. P. Young, B. A. Leggett

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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, 0.66, P0.0001), with higher methylation distally (ESR1, P0.0001). On multivariate analysis, type A methylation was inversely associated with colorectal adenomas (odds ratio0.23, P0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio5.1, P0.009), 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.

Original languageEnglish
Pages (from-to)1653-1662
Number of pages10
JournalOncogene
Volume29
Issue number11
DOIs
Publication statusPublished - Mar 2010

Keywords

  • Carcinogenesis
  • Colorectal cancer
  • DNA methylation
  • Epigenetics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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