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

// Sergio Alonso 1, 2 , Yuichi Dai 1, 3, 4 , Kentaro Yamashita 1 , Shina Horiuchi 1 , Tomoko Dai 1, 3 , Akihiro Matsunaga 1 , Rosa Sanchez-Munoz 1 , Cristina Bilbao-Sieyro 5 , Juan Carlos Diaz-Chico 5 , Andrei V. Chernov 6 , Alex Y. Strongin 6 , Manuel Perucho 1, 2, 7 1 Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA 2 Institute of Predictive and Personalized Medicine of Cancer (IMPPC), IGTP, Badalona, Barcelona, Spain 3 Dept. of Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan 4 Dept. of Diagnostic Pathology, Tsukuba Memorial Hospital, Tsukuba, Ibaraki, Japan 5 Dept. of Biochemistry and Molecular Biology, Cancer Research Institute of The Canary Islands, University of Las Palmas de Gran Canaria, Spain 6 Cancer Research Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA 7 Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain Correspondence to: Manuel Perucho, e-mail: mperucho@imppc.org Keywords: KRAS mutations, TP53 mutations, MGMT , O 6 -methylguanine-DNA methyltransferase, ADAMTS14 , CRC, colorectal cancer Received: November 28, 2014 Accepted: December 04, 2014 Published: February 02, 2015 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 × 10 −5 ), thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America.