Sex-specific functional UGT2B17 deletion polymorphism increases risk for lung cancer.

A180

UGT2B17 is a phase II metabolizing enzyme that mediates the detoxification of the tobacco smoke carcinogen, NNK, by converting its major metabolite, NNAL, to its glucuronide, NNAL-Gluc. A common deletion allele (~30 % prevalence in whites) encompassing the entire UGT2B17 gene was identified and found to reduce the rate of NNAL glucuronidation in human liver microsomes in vitro. The goal of the present study was to determine if the UGT2B17 deletion genotype is associated with reduced rates of glucuronidation in vivo and with increased risk for lung cancer. We developed a novel multiplex real-time PCR assay to genotype the UGT2B17 gene deletion. In a screening of 82 white smokers, the urinary concentrations of NNAL and NNAL-Gluc were measured. A significant decrease in urinary NNAL-Gluc to NNAL ratio was observed among smokers with the UGT2B17 deletion [(0/0)] genotype when compared to smokers with at least one intact UGT2B17 allele (p-value=0.049). This association was only observed in females (p-value=0.058); no association was observed in males (p-value=0.597). In an analysis of 398 white subjects with newly-diagnosed primary lung cancer and 697 white controls, a significant increase in risk for lung cancer was observed in women with the UGT2B17 (0/0) genotype when compared to women with at least one intact UGT2B17 allele (OR=2.0, 95 % CI=1.04-3.75). This association was specific for women with adenocarcinoma (OR=3.2, 95 % CI=1.48-6.90). No association was observed between the (0/0) genotype and risk for lung cancer (OR=0.7, 95 % CI=0.39-1.39) or specifically for lung adenocarcinoma (OR=1.3, 95 % CI=0.58-3.09) in men. The sex-specific association of the UGT2B17 gene deletion polymorphism with urinary NNAL glucuronidation phenotype and increased risk for lung adenocarcinoma is consistent with animal model studies demonstrating that NNAL is a selective inducer of lung adenocarcinoma, and with in vitro studies demonstrating that UGT2B17 may be down-regulated by male androgens. This is the first study demonstrating a sex-specific link between a common genetic variant and lung cancer risk.