Methylation of O(6)-methylguanine-DNA methyltransferase gene is associated significantly with K-ras mutation, lymph node invasion, tumor staging, and disease free survival in patients with gastric carcinoma.
BACKGROUND
O(6)-methylguanine-DNA methyltransferase (MGMT) can remove O(6)alkylG DNA adducts. If they are not removed, then the adducts mispair with T during DNA replication, resulting in G-to-A mutation. Interrelations between MGMT gene inactivation by promoter methylation, K-ras mutation, and clinicopathologic features in patients with gastric carcinoma were studied.


METHODS
Surgically removed tumor tissues from 79 patients were analyzed with MGMT methylation by genomic DNA modification and methylation specific polymerase chain reaction analysis, K-ras mutation by mutant allele specific amplification, TNM classification according to the International Union Against Cancer system, and MGMT protein expression by immunohistochemistry.


RESULTS
MGMT-promoter methylation was found in 18 of 79 tumors. Among those 18 tumors, K-ras mutations were found in 33% and 11% of tumors at codons 12 and 13, respectively, corresponding to 20 times and 7 times greater rates of mutation compared with unmethylated tumors. MGMT methylation was associated significantly with lymph node invasion (P < 0.01), tumor stage (P < 0.03) and 5-year disease free survival (P < 0.02). MGMT protein expression was detected in intestinal metaplasia and adenocarcinoma samples, whereas no expression was detected in normal foveolar cells.


CONCLUSIONS
MGMT-promoter methylation in patients with gastric carcinoma was associated significantly with point mutations of K-ras at codons 12 and 13, lymph node invasion, tumor stage, and disease free survival. These associations indicate a significant role of MGMT methylation during gastric carcinogenesis.
Park
T J
TJ
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
Han
S U
SU
Cho
Y K
YK
Paik
W K
WK
Kim
Y B
YB
Lim
I K
IK
D000230:Adenocarcinoma / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015197:Carcinogenicity Tests; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D011905:Genes, ras; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
D019853:O(6)-Methylguanine-DNA Methyltransferase