Relationship between genetic polymorphisms of drug-metabolizing enzymes (CYP1A1, CYP2E1, GSTM1, and NAT2), drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer.
BACKGROUND
Genetic polymorphisms of drug-metabolizing enzymes have recently been shown to affect susceptibility to chemical carcinogenesis. However, the molecular mechanisms of individual susceptibility to gastric cancer have not been fully understood. Therefore, we studied the relationship between the genetic polymorphisms of drug-metabolizing enzymes, drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer.


METHODS
The genotypes of cytochromes P450 ( CYP) 1A1 and 2E1, glutathione S-transferase ( GST) M1, and N-acetyltransferase ( NAT) were investigated by polymerase chain reaction (PCR), allele-specific PCR, or restriction fragment length polymorphism (RFLP) following PCR in 146 Japanese patients with gastric cancer (67 intestinal-type and 79 diffuse-type carcinomas) and 177 autopsied controls. In addition, p53 gene point mutations of exons 5 through 9 in gastric cancer tissues were determined.


RESULTS
The frequency of either being a habitual drinker or having a CYP2E1(*) 1A/(*) 1A genotype was significantly higher in patients with intestinal-type gastric cancer than in control subjects. The difference between the frequencies of habitual drinkers with the CYP2E1(*) 1A/(*) 1A genotype and non-drinkers with the CYP2E1(*) 5B allele was much more significant in the intestinal-type cancer versus the control group. Among intestinal-type cancer patients with the CYP2E1(*) 1A/(*) 1A genotype, p53 point mutations were significantly more frequent in the group of habitual drinkers than in that of non-drinkers. On the other hand, the combination of GSTM1 null and CYP2E1(*) 1A/(*) 1A genotypes increased the risk for diffuse-type gastric cancer, but had no influence on the frequency of p53 gene mutations.


CONCLUSIONS
The present study suggests that individuals with both the CYP2E1(*) 1A/(*) 1A genotype and a history of habitual drinking have an increased risk of intestinal-type gastric cancer with a high frequency of p53 gene point mutations in the gastric mucosa.
Suzuki
Shioto
S
Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Muroishi
Youko
Y
Nakanishi
Isao
I
Oda
Yoshio
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011110:Polymorphism, Genetic; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics*
D001189:Aryl Hydrocarbon Hydroxylases; D001191:Arylamine N-Acetyltransferase; D019363:Cytochrome P-450 CYP1A1; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; C478900:NAT2 protein, human