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Title: Methylation of MGMT and ADAMTS14 in normal colon mucosa: Biomarkers of a field defect for cancerization preferentially targeting elder African-Americans
Authors: Alonso, Sergio
Dai, Yuichi
Yamashita, Kentaro
Horiuchi, Shina
Dai, Tomoko
Matsunaga, Akihiro
Sánchez-Muñoz, Rosa
Bilbao-Sieyro, Cristina 
Daz-Chico, Juan Carlos 
Chernov, Andrei V.
Strongin, Alex Y.
Perucho, Manuel
UNESCO Clasification: 32 Ciencias médicas
320101 Oncología
Keywords: Cpg Island Hypermethylation
Gene O-6-Methylguanine-Dna Methyltransferase
Dna Mismatch Repair
Promoter Hypermethylation, et al
Issue Date: 2015
Journal: Oncotarget 
Abstract: Somatic hypermethylation of the O-6-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 x 10(-5)), thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America.
ISSN: 1949-2553
DOI: 10.18632/oncotarget.2852
Source: Oncotarget[ISSN 1949-2553],v. 6 (5), p. 3420-3431
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