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A polymorphism at codon 160 of human O6 methylguanine-DNA methyltransferase gene in young patients with adult type cancers and functional assay
Department of Pathology, University of Tokyo Faculty of Medicine 7-3-I Hongo, Bunkyo-ku, Tokyo 113, Japan
1To whom correspondence should be addressed
O6 methyltransferase (MGMT) plays an important role in repair of alkylating agent-induced DNA damage. Among the alkylatlon 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 nucteotide 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 he 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 tenninal. 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 
15% of the population, although this does not rule out a possible influence in other tissues.
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