Inactivation of O6-methylguanine-DNA methyltransferase by promoter CpG island hypermethylation in gastric cancers.
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.
Bae
S I
SI
Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Seoul 110-799, Korea.
Lee
H S
HS
Kim
S H
SH
Kim
W H
WH
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
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