A polymorphism at codon 160 of human O6-methylguanine-DNA methyltransferase gene in young patients with adult type cancers and functional assay.
O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in repair of alkylating agent-induced DNA damage. Among the alkylation products of DNA, O6-methylguanine is one of the most critical lesions leading to the induction of mutations. The enzyme MGMT transfers the methyl group from O6-methylguanine of DNA to its own cysteine residue. Although mutations of other DNA repair genes involved in nucleotide excision repair and mismatch repair have been proven to be related to human tumorigenesis, the question of whether MGMT gene mutation might play a role in human carcinogenesis has hitherto not been elucidated. If there is a population with decreased enzyme activity due to defective MGMT gene, the affected individuals should be at risk of developing cancer early in life because of an increased susceptibility to alkylating agents. To test this hypothesis, germ line mutations of the MGMT gene were investigated in 12 young patients with adult type cancers (mean, 16.7 years old, 8 hepatocellular carcinomas, 3 gastric cancers, 1 cholangiocellular carcinoma) and 28 elderly patients who died of non-cancer diseases as controls (mean, 66 years old). A point mutation at codon 160 in exon 5, GGA to AGA, converting glycine to arginine was found in three of the young patients (25%), while the same mutation was found in three out of 28 (10.7%) in the control group. The mutated codon was located 15 codons from a functional cysteine residue toward the carboxyl terminal. Investigation of enzyme function, even in cases of bi-allelic mutation, revealed comparable activities for both mutated and wild type MGMT. Thus, we conclude the mutation is a normal polymorphism of the MGMT gene, present in approximately 15% of the population, although this does not rule out a possible influence in other tissues.
Imai
Y
Y
Department of Pathology, University of Tokyo Faculty of Medicine, Japan.
Oda
H
H
Nakatsuru
Y
Y
Ishikawa
T
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics*; D002648:Child; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics*; D003062:Codon / Q000235:genetics; D003545:Cysteine; D017931:DNA Primers; D005091:Exons; D005260:Female; D005998:Glycine; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D019853:O(6)-Methylguanine-DNA Methyltransferase; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012016:Reference Values; D013154:Spleen / Q000201:enzymology; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics*
D003062:Codon; D017931:DNA Primers; D001120:Arginine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003545:Cysteine; D005998:Glycine