Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking.
The enzyme NAD(P)H:quinone oxidoreductase (NQO1) catalyses bioreduction and bioactivation reactions. A mutation in the NQO1 gene had previously been demonstrated in a cancer cell line with reduced NQO1 activity. In this study, several regions of the NQO1 locus were examined for constitutional variation at the DNA level. The previously described mutation in exon 6 was detected by the single-strand conformation polymorphism technique. This was confirmed by sequencing to result from a C-->T substitution. Genotype analysis in the Centre d'Etude Polymorphisme Humain (CEPH) reference panel revealed two alleles with frequencies of 0.87 and 0.13 and demonstrated Mendelian transmission. Genotype distributions were consistent with Hardy-Weinberg equilibrium. Linkage analysis mapped the gene locus to chromosome 16q. NQO1 was felt to be a candidate gene for the susceptibility to lung cancer, given its potential role in protection against carcinogenic compounds. The frequency of NQO1 variants was examined in 150 lung cancer cases and in two reference populations. The allele distribution in CEPH parent controls was significantly different from cases (chi 2 = 5.52, p = 0.019), but no difference was noted between cases and a healthy local reference population. When the local reference distribution was stratified on smoking status, a significant difference was observed (chi 2 = 3.88, p = 0.048).(ABSTRACT TRUNCATED AT 250 WORDS)
Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
E A
EA
Rosvold
K A
KA
McGlynn
E D
ED
Lustbader
K H
KH
Buetow
D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D017931:DNA Primers; D005091:Exons; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008969:Molecular Sequence Data; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D012907:Smoking / Q000453:epidemiology / Q000235:genetics*
D017931:DNA Primers; D005819:Genetic Markers; D016660:NAD(P)H Dehydrogenase (Quinone)