Clinical Research Papers:
Methylation of MGMT and ADAMTS14 in normal colon MUCOSA: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans
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Sergio Alonso1,2, Yuichi Dai1,3,4, Kentaro Yamashita1, Shina Horiuchi1, Tomoko Dai1,3, Akihiro Matsunaga1, Rosa Sánchez-Muñoz1, Cristina Bilbao-Sieyro5, Juan Carlos Díaz-Chico5, Andrei V. Chernov6, Alex Y. Strongin6, Manuel Perucho1,2,7
1Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA
2Institute of Predictive and Personalized Medicine of Cancer (IMPPC), IGTP, Badalona, Barcelona, Spain
3Dept. of Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
4Dept. of Diagnostic Pathology, Tsukuba Memorial Hospital, Tsukuba, Ibaraki, Japan
5Dept. of Biochemistry and Molecular Biology, Cancer Research Institute of The Canary Islands, University of Las Palmas de Gran Canaria, Spain
6Cancer Research Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA
7Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Manuel Perucho, e-mail: [email protected]
Keywords: KRAS mutations, TP53 mutations, MGMT, O6-methylguanine-DNA methyltransferase, ADAMTS14, CRC, colorectal cancer
Received: November 28, 2014 Accepted: December 04, 2014 Published: February 02, 2015
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.
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