Identification of an NAD(P)H: Quinone oxidoreductase polymorphism and its association with lung cancer and smoking

The enzyme NAD(P)H: Quinone oxidoreductase (NQ01) catalyses bioreduction and bioactivation reactions. A mutation in the NQ01 gene had previously been demonstrated in a cancer cell line with reduced NQ01 activity. In this study, several regions of the NQ01 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. NQ01 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 NQ01 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 (X 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 (X ²=3.88, p=0.048). The distribution in smokers was more similar to the lung cancer cases, and the non-smokers more similar to the distribution in CEPH parents who are predominantly non-smokers. These results provide preliminary evidence for a possible relation between NQ01 variation and smoking-related morbidity or behaviour.