title: Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans.
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.
authors: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), IGTP, Badalona, Barcelona, Spain.
authors: Sergio
authors: S
authors: Alonso
authors: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.|Dept. of Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.|Dept. of Diagnostic Pathology, Tsukuba Memorial Hospital, Tsukuba, Ibaraki, Japan.
authors: Yuichi
authors: Y
authors: Dai
authors: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.
authors: Kentaro
authors: K
authors: Yamashita
authors: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.
authors: Shina
authors: S
authors: Horiuchi
authors: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.|Dept. of Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
authors: Tomoko
authors: T
authors: Dai
authors: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.
authors: Akihiro
authors: A
authors: Matsunaga
authors: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.
authors: Rosa
authors: R
authors: Sánchez-Muñoz
authors: Dept. of Biochemistry and Molecular Biology, Cancer Research Institute of The Canary Islands, University of Las Palmas de Gran Canaria, Spain.
authors: Cristina
authors: C
authors: Bilbao-Sieyro
authors: Dept. of Biochemistry and Molecular Biology, Cancer Research Institute of The Canary Islands, University of Las Palmas de Gran Canaria, Spain.
authors: Juan Carlos
authors: JC
authors: Díaz-Chico
authors: Cancer Research Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.
authors: Andrei V
authors: AV
authors: Chernov
authors: Cancer Research Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.
authors: Alex Y
authors: AY
authors: Strongin
authors: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), IGTP, Badalona, Barcelona, Spain.|Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors: Manuel
authors: M
authors: Perucho
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000071096:ADAMTS Proteins; D000230:Adenocarcinoma / Q000201:enzymology / Q000208:ethnology* / Q000235:genetics*; D001741:Black or African American / Q000235:genetics*; D000367:Age Factors; D003106:Colon / Q000201:enzymology*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000208:ethnology* / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology*; D053842:Microsatellite Instability; D009154:Mutation; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014481:United States / Q000453:epidemiology
chemical_list: C117307:KRAS protein, human; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C447060:ADAMTS14 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D045643:DNA Repair Enzymes
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