Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas
Autor: | Susan C. Abraham, Tsung Teh Wu, Stanley R. Hamilton, Sang Woo Juhng, Jong Hee Nam, Chan Choi, Asif Rashid, Seun Ja Park, Jae Sung Seo, Jae Hyuk Lee |
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Rok vydání: | 2004 |
Předmět: |
Adenoma
Cancer Research medicine.medical_specialty Genes APC Adenocarcinoma Biology Gene mutation medicine.disease_cause Reference Values Stomach Neoplasms Internal medicine Genetics medicine Carcinoma Humans Epigenetics Molecular Biology Adaptor Proteins Signal Transducing Metaplasia Genes p16 Nuclear Proteins Microsatellite instability Methylation DNA Methylation medicine.disease digestive system diseases Neoplasm Proteins Intestines Endocrinology CpG site Gastric Mucosa Cancer research CpG Islands Carrier Proteins MutL Protein Homolog 1 Carcinogenesis Microsatellite Repeats |
Zdroj: | Oncogene. 23:4646-4654 |
ISSN: | 1476-5594 0950-9232 |
Popis: | Gastric carcinogenesis involves multiple genetic and epigenetic alterations. Epigenetic silencing of tumor-related genes due to CpG island methylation (CIM) has been recently reported in gastric cancer, but the role in precursor lesions is not well understood. We analysed the methylation status of the tumor suppressor gene p16, the DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using methylation-specific polymerase chain reaction in 35 polypoid adenomas and 46 flat dysplasias unassociated with carcinoma, 34 early adenocarcinomas (T1N0M0) and associated adenomas/dysplasias, and corresponding adjacent non-neoplastic mucosa. The extent of CIM was defined by the fraction of methylated loci (methylation index), and compared with previously characterized genetic alterations (microsatellite instability (MSI) and APC gene mutation). We found that methylation of p16 was more frequent in adenocarcinoma-associated dysplasias/adenomas (29%) and adenocarcinomas (44%) as compared to flat dysplasias (4%) and adenomas (18%) unassociated with adenocarcinoma (P=0.001). The mean methylation index increased from normal/chronic gastritis (CG) mucosa (0.09) to intestinal metaplasia (IM) (0.16), flat dysplasias (0.40) or polypoid adenomas (0.41) unassociated with carcinoma, dysplasias/adenomas associated with carcinoma (0.44), and adenocarcinomas (0.44). There was no difference in frequencies of high-level CpG island methylation (CIM-H, methylation indexor =0.5) among flat dysplasias (50%) and polypoid adenomas (51%) unassociated with carcinoma, dysplasias/adenomas associated with adenocarcinoma (47%), and adenocarcinoma (47%). CIM-H was present in 15% of IM, but not in normal/CG mucosa. There was a significant correlation between methylation of hMLH1 and high-level of microsatellite instability (MSI-H): methylation of hMLH1 was present in 71% of MSI-H tumors, but only 8% of MSI-low tumors and 13% of microsatellite-stable tumors (P=0.0001). There was no statistical difference between methylation index and APC mutation. Our results indicate that concurrent promoter methylation is an early and frequent event in gastric tumorigenesis, including both MSI-H and microsatellite-stable neoplasms. Methylation of the p16 gene may contribute to the malignant transformation of gastric precursor lesions. |
Databáze: | OpenAIRE |
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