Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans

Oncotarget. 2015 Feb 20;6(5):3420-31. doi: 10.18632/oncotarget.2852.

Abstract

Somatic hypermethylation of the O6-methylguanine-DNA methyltransferase gene (MGMT) was previously associated with G > A transition mutations in KRAS and TP53 in colorectal cancer (CRC). We tested the association of MGMT methylation with G > A mutations in KRAS and TP53 in 261 CRCs. Sixteen cases, with and without MGMT hypermethylation, were further analyzed by exome sequencing. No significant association of MGMT methylation with G > A mutations in KRAS, TP53 or in the whole exome was found (p > 0.5 in all comparisons). The result was validated by in silico comparison with 302 CRCs from The Cancer Genome Atlas (TCGA) consortium dataset. Transcriptional silencing associated with hypermethylation and stratified into monoallelic and biallelic. We also found a significant clustering (p = 0.001) of aberrant hypermethylation of MGMT and the matrix metalloproteinase gene ADAMTS14 in normal colonic mucosa of CRC patients. This suggested the existence of an epigenetic field defect for cancerization disrupting the methylation patterns of several loci, including MGMT or ADAMTS14, that may lead to predictive biomarkers for CRC. Methylation of these loci in normal mucosa was more frequent in elder (p = 0.001) patients, and particularly in African Americans (p = 1 × 10-5), thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics*
  • ADAMTS Proteins
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / ethnology*
  • Adenocarcinoma / genetics*
  • African Americans / genetics*
  • Age Factors
  • Colon / enzymology*
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / ethnology*
  • Colorectal Neoplasms / genetics*
  • DNA Methylation*
  • DNA Modification Methylases / genetics*
  • DNA Repair Enzymes / genetics*
  • Databases, Genetic
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • Intestinal Mucosa / enzymology*
  • Microsatellite Instability
  • Mutation
  • Phenotype
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA, Messenger / genetics
  • Retrospective Studies
  • Risk Factors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics*
  • United States / epidemiology

Substances

  • KRAS protein, human
  • RNA, Messenger
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • DNA Modification Methylases
  • MGMT protein, human
  • ADAM Proteins
  • ADAMTS Proteins
  • ADAMTS14 protein, human
  • Proto-Oncogene Proteins p21(ras)
  • DNA Repair Enzymes