Human debrisoquine hydroxylase gene polymorphisms in cancer patients and controls.
The extensive metabolizer phenotype of debrisoquine has been associated with increased risk of lung cancer, and it has been proposed that a molecular test for this phenotype is feasible. DNA restriction fragment length polymorphisms of the human debrisoquine 4-hydroxylase gene locus (CYP2D6), and the metabolic phenotype for debrisoquine have been studied in a group of healthy volunteers, a group of lung cancer patients and two control groups (chronic obstructive pulmonary disease patients and patients with cancers at sites other than the lung). Confirmation of four distinct XbaI allelic fragments (44, 29, 16/9 and 11.5 kb), previously identified among caucasians, was obtained. The 29 kb alleles were the most frequently observed in both poor and extensive metabolizers of debrisoquine. Alleles of 44 kb were found with approximately equal frequency among both poor and extensive metabolizers. The data are consistent with the hypothesis that the 11.5 and 44 kb fragments are associated with mutant alleles of the CYP2D6 gene, but the power of phenotype prediction by these alleles was less than that previously reported for a European (Swiss-German) population. Similarly, the data also show that 8% of 29 kb homozygotes are poor metabolizers (indicating that at least 28% of 29 kb fragments are also associated with mutant alleles) and are not therefore informative for predicting the debrisoquine phenotype. The 16/9 allele may represent either wild-type or mutant alleles. Restriction fragments of 44 kb were found more frequently among cancer patients and chronic obstructive pulmonary disease patients (30%) than among the healthy volunteer group (7%). Genotypes observed were not related to lung tumor histology. Furthermore, at least three EcoRI alleles were found to be in linkage disequilibrium with the 'mutant' 44 kb allele. These data suggest that the 44 kb allele can comprise three distinct haplotypes, in contrast to studies of a European population. These studies indicate that no single mutant CYP2D6 allele as determined by EcoRI appears to be associated with lung cancer, despite the findings that these patients are invariably of the extensive metabolizer phenotype.
Sugimura
H
H
Laboratory of Human Carcinogenesis, NCI, NIH, Bethesda, MD 20892.
Caporaso
N E
NE
Shaw
G L
GL
Modali
R V
RV
Gonzalez
F J
FJ
Hoover
R N
RN
Resau
J H
JH
Trump
B F
BF
Weston
A
A
Harris
C C
CC
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003647:Debrisoquin / Q000378:metabolism; D015246:Deoxyribonuclease EcoRI; D015252:Deoxyribonucleases, Type II Site-Specific; D005260:Female; D005796:Genes; D006801:Humans; D008173:Lung Diseases, Obstructive / Q000201:enzymology / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D012016:Reference Values
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D015246:Deoxyribonuclease EcoRI; C025580:endodeoxyribonuclease XBAI; D015252:Deoxyribonucleases, Type II Site-Specific; D003647:Debrisoquin