Polymorphisms in the human CYP1A1 gene as susceptibility factors for lung cancer: exon-7 mutation (4889 A to G), and a T to C mutation in the 3'-flanking region.
Genetic differences in the metabolism of carcinogens may codetermine individual predisposition to cancer. Cytochrome P-4501A1 (CYP1A1) metabolically activates precarcinogens in cigarette smoke, such as benzo(a)pyrene, which is also an inducer of CYP1A1. Two point mutations have been reported, m1 in the 3'-flanking region (6235T to C), and m2 within exon 7 (4889A to G), the latter leading to an isoleucine to valine exchange. In the Japanese population m1 and m2 are correlated with lung cancer, suggesting an increased susceptibility to cigarette smoking related lung cancer. We studied 142 lung cancer and 171 reference patients in an ethnically homogeneous German group for m1 and m2 mutations by restriction fragment length polymorphism and allele-specific polymerase chain reaction, respectively. No statistically significant difference was found in the distribution of m1 alleles between lung cancer and controls; the frequency was 8.5% and 7.3% of the alleles, respectively (odds ratio = 1.17). A trend to an overrepresentation of m1 alleles was observed among 52 squamous cell carcinoma patients (odds ratio = 1.65). In contrast, the frequency of m2 alleles in lung cancer patients was twofold higher (6.7%) than in the reference group (3.2%; odds ratio = 2.16; 95% confidence limits 0.96-5.11, P = 0.033); the odds ratio of m2 alleles in squamous cell carcinoma was 2.51 (95% confidence limits 0.85-7.05, P = 0.05). There was a close genetic linkage of m2 to m1 (10 of 11 reference patients), but a significantly higher number of cancer patients showed no linkage compared to the controls (odds ratio = 8.89, 95% confidence limits 0.83-433, P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)
Drakoulis
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N
Institut für Klinische Pharmakologie, Medizinische Fakultät (Charité), Humboldt-Universität zu Berlin, Germany.
Cascorbi
I
I
Brockmöller
J
J
Gross
C R
CR
Roots
I
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics; D002283:Carcinoma, Bronchogenic / Q000201:enzymology / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D005796:Genes; D020022:Genetic Predisposition to Disease; D006801:Humans; D008171:Lung Diseases / Q000201:enzymology / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D016017:Odds Ratio; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D044465:White People / Q000235:genetics
D002273:Carcinogens; D009363:Neoplasm Proteins; D003577:Cytochrome P-450 Enzyme System