Mutations of O6-methylguanine-DNA methyltransferase gene in esophageal cancer tissues from Northern China.
Epidemiologic studies have implicated the involvement of environmental factors in the etiology of esophageal cancer (EC). Our previous data have indicated that EC patients and their blood relatives show genomic instability and are deficient in repair of DNA damage induced by N-nitroso-compounds and related genotoxic agents. Thus, exposure to high levels of N-alkylnitrosamines, which are known animal carcinogens and which induce alkyl adducts in DNA, may be causally linked to EC. Among the alkyl adducts, O6-alkylguanine was shown to be the critical one related to carcinogenic lesions; its repair varies widely in a tissue-specific fashion. O6-methylguanine-DNA methyltransferase (MGMT) is responsible for its repair. Hence, inactivating mutations in this protein would impair the efficiency of the repair process. To screen for possible mutations in the MGMT polypeptide in EC patients, we analyzed a highly conserved region of the MGMT gene in 40 EC tissues and lymphocytes of 6 high-risk EC family members from high EC areas of Northern China by polymerase chain reaction single-strand conformation polymorphism and by direct sequencing of PCR products. Ten base substitutions (point mutations) within 8 codons of 7 EC samples were identified. However, no germline mutation was found in the high EC families studied so far. Concurrent study in 30 pairs of fresh EC tissues and their adjacent normal mucosa by Southern blot and Western blot analyses showed deletion of the MGMT gene in 2 samples. Thus, the high frequency of mutations (7/40) and deletions (2/30) of the MGMT gene may be partially responsible for the overall high mutation rate observed in EC tissues.
Wang
L
L
Department of Cell Biology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing.
Zhu
D
D
Zhang
C
C
Mao
X
X
Wang
G
G
Mitra
S
S
Li
B F
BF
Wang
X
X
Wu
M
M
D001483:Base Sequence; D015139:Blotting, Southern; D002681:China; D004938:Esophageal Neoplasms / Q000235:genetics*; D006801:Humans; D008780:Methyltransferases / Q000235:genetics*; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA
D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase