CYP2A6 genetic score, nicotine metabolism and lung cancer

ABSTRACT In the United States this year, an estimated 235,760 new lung cancer cases will be diagnosed. The vast majority of those are attributable to smoking. However, only 11-24% of smokers will develop lung cancer and the risk among smokers varies significantly. Individual differences in nicotine metabolism can influence that risk by influencing the intensity of smoking. The primary catalyst of nicotine metabolism is CYP2A6, and we have demonstrated an association of CYP2A6 activity with the risk of lung cancer. These data are from a subcohort of ~2200 smokers with nicotine metabolism biomarker data in the Multiethnic Cohort (MEC). The risk of lung cancer varies across racial/ethnic group as does the contribution of CYP2A6 activity to that risk. In this project, we propose to develop a genetic score to predict CYP 2A6-catalyzed nicotine metabolism and to determine the association of that score with the lung cancer risk of ever smokers in the MEC. The gene that encodes CYP2A6 is notoriously polymorphic. The high homology between CYP2A6 and the pseudogene CYP2A7, the many variant alleles of each, and their unique distribution by racial/ethnic group complicates the accurate genotyping of functional variants. However, correctly characterizing an individual's CYP2A6 alleles is integral to the genotype-guided prediction of nicotine metabolism, and to the complete characterization of CYP2A6 variation in multiethnic populations. The related gene CYP2D6 has similar genetic complexities and is equally challenging to genotype. However, recent advances have led to the successful application of long- range sequencing approaches to accurate CYP2D6 variant calling. We propose to use a similar targeted sequencing approach to characterize CYP2A6 genetic diversity across racial/ethnic groups. The improved characterization of CYP2A6 will allow the comprehensive study of the role of CYP2A6 variants in tobacco- related lung cancer and ultimately better identify those at greatest risk for lung cancer and target them for prevention strategies. The overall hypothesis of our research is that variation in CYP2A6 activity contributes to the observed racial/ethnic disparities in lung cancer risk, and that the relative contribution of CYP2A6 activity to risk varies by racial/ethnic group based on the prevalence of metabolically important CYP2A6 variants. The following specific aims are proposed: Aim 1: To characterize the genetic diversity of CYP2A6 in Native Hawaiians relative to Japanese Americans and Whites. CYP2A6 (and CYP2A7) will be sequenced using the PacBio SMRTbellTM Sequencing platform. Aim 2: To develop a CYP2A6 genetic score to predict CYP2A6 nicotine metabolism in the MEC. Aim 3: To investigate the association of the CYP2A6 genetic score developed in Aim 2 with lung cancer in MEC ever smokers with GWAS data.