Dataset Information

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.

SUBMITTER: Alonso S

PROVIDER: S-EPMC4413663 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Alonso Sergio S Dai Yuichi Y Yamashita Kentaro K Horiuchi Shina S Dai Tomoko T Matsunaga Akihiro A Sánchez-Muñoz Rosa R Bilbao-Sieyro Cristina C Díaz-Chico Juan Carlos JC Chernov Andrei V AV Strongin Alex Y AY Perucho Manuel M

Oncotarget 20150201 5

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 > ...[more]

PMID: 25638164

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Project description:The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide-spectrum molecular studies that delve into the impact of T2DM-related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2DM. We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes-related metabolic and signaling processes. Proteomic approaches highlighted several cancer-related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD/YAP-TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high-glucose conditions. In conclusion, T2DM associates with deregulation of cancer-related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD/YAP-TAZ complex as a potential driver.

Project description:It has been shown in some articles that genetic and epigenetic abnormalities cannot only be found in tumor tissues but also in adjacent regions that appear histologically normal. This phenomenon is metaphorically called field cancerization or field defect. Field cancerization is regarded as clinically significant because it is assumed to be an important factor in local recurrence of cancer. As the field showing these molecular abnormalities may not be removed completely by surgery, these changes might lead to neoplasms and subsequent transformation to a tumor. We aimed to investigate the applicability of the methylation status of six tumor suppressor genes as biomarkers for detecting field cancerization in breast cancer.The promoter methylation status of CCND2, DAPK1, GSTP1, HIN-1, MGMT and RASSF1A was determined by methylation-sensitive high-resolution melting (MS-HRM) analysis. MS-HRM methods for CCND2, MGMT and RASSF1A were developed in-house, primer sequences for DAPK1, GSTP1 and HIN-1 have already been published. Biopsy samples were taken from tumor, tumor-adjacent and tumor-distant tissue from 17 breast cancer patients. Normal breast tissues of four healthy women served as controls.All MS-HRM methods proved to be very sensitive. LODs were in the range from 0.1 to 1.5 %, LOQs ranged from 0.3 to 5.3 %. A total of 94 %, 82 % and 65 % of the tumors showed methylation of RASSF1A, HIN-1 and MGMT promoters, respectively. The methylation status of these promoters was significantly lower in tumor-distant tissues than in tumor tissues. Tumor-adjacent tissues showed higher methylation status of RASSF1A, HIN-1 and MGMT promoters than tumor-distant tissues, indicating field cancerization. The methylation status of the HIN-1 promoter in tumor-adjacent tissues was found to correlate strongly with that in the corresponding tumors (r?=?0.785, p?<?0.001), but not with that in the corresponding tumor-distant tissues (r?=?0.312, p?=?0.239).Among the gene promoters investigated, the methylation status of the HIN-1 promoter can be considered the best suitable biomarker for detecting field cancerization. Further investigation is needed to test whether it can be used for defining surgical margins in order to prevent future recurrence of breast cancer.

Dataset Information

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

Publications

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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