title: Inactivation of O6-methylguanine-DNA methyltransferase by promoter CpG island hypermethylation in gastric cancers.
abstract: Promoter hypermethylation of CpG islands in tumour suppressor genes can lead to transcriptional inactivation. To investigate the association between methylation and expression at O6-methylguanine-DNA methyltransferase, we performed methylation-specific PCR and immunohistochemistry in 149 gastric carcinomas. Promoter methylation was found in 14.1% of tumours and loss of expression was detected in 11.4% of tumours. To examine correlation between the O6-methylguanine-DNA methyltransferase expression and the clinical data, we investigated O6-methylguanine-DNA methyltransferase expression in 315 consecutive gastric carcinomas. A similar frequency of loss of O6-methylguanine-DNA methyltransferase expression was confirmed in these cases. The loss of O6-methylguanine-DNA methyltransferase expression was significantly associated with pTNM stage (P=0.037), tumour invasion (P=0.02), microsatellite instability (P=0.041) and overall survival (P=0.01). Among 11 gastric cancer cell lines, SNU-620 showed the loss of O6-methylguanine-DNA methyltransferase expression as well as promoter methylation. After treatment with 5-aza-2-deoxycytidine, a demethylating agent, SNU-620 re-expressed O6-methylguanine-DNA methyltransferase mRNA. In summary, we suggest that during gastric carcinogenesis, the loss of O6-methylguanine-DNA methyltransferase expression frequently occurs via the hypermethylation of the CpG islands of the promoter region, and that this is significantly associated with the clinicopathological characteristics.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Seoul 110-799, Korea.
authors.forename: S I
authors.initials: SI
authors.lastname: Bae
authors.forename: H S
authors.initials: HS
authors.lastname: Lee
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: W H
authors.initials: WH
authors.lastname: Kim
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D017931:DNA Primers / Q000737:chemistry; D000077209:Decitabine; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013270:Stomach / Q000201:enzymology; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D013447:Sulfites / Q000494:pharmacology; D015996:Survival Rate; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013447:Sulfites; D000077209:Decitabine; D015254:DNA Modification Methylases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D001374:Azacitidine; C009279:sodium bisulfite