Abstract IA15: Role of environment in genetic predisposition: Lessons from tobacco studies

Abstract While it is well recognized that tobacco smoke is the leading cause of preventable cancer mortality and morbidity, efforts to control its impact on population health have been only partially successful. In this talk we describe population characteristics relating to nicotine dependence. Among those who initiate tobacco smoking, about 80% become dependent, but even among this set there is a variable degree of dependence, affecting the propensity to quit. Twin and family studies have shown a very strong impact of genetic factors on smoking behavior, which is a relatively easier behavior to measure. Therefore, massive studies involving about 500,000 individuals have now been completed and these give comprehensive descriptions of the genetic profiles that influence tobacco smoking initiation, smoking behavior, and cessation. Genetic analysis of lung cancer risk and nicotine dependence identified a region of chromosome 15q25.1 that is strongly implicated in influence risk for both diseases. Further research using retrospective data from population studies and tobacco cessation trials showed a profound influence of genotypes on propensity to quit smoking and an interaction between efficacy of pharmacologic intervention and successful tobacco cessation. These findings, along with observations about similar striking effects of CYP2A6 variation on smoking behavior, have led to the design and conduct of novel studies that integrate genetic information into the allocation of participants into tobacco cessation trials, which we will discuss. As it is the primary driver of lung cancer risk, tobacco smoking is a key driver in identifying individuals who will benefit from low-dose spiral CT, which is among the only screening protocols that has a proven impact in reducing overall mortality and which also results in a striking stage shift for lung cancer and a substantial reduction in lung cancer-specific mortality. Despite the individual benefits of screening, the cost of lung cancer screening remains high and current guidelines, which restrict access to the highest risk participants, exclude from consideration most cases of lung cancer. Towards building improved risk prediction models for lung cancer, we discuss results from lung cancer genetic studies that have identified multiple genetic factors predisposing to lung cancer risk and that can identify biomarkers and host-specific factors that associate with lung cancer risk and identify more susceptible individuals. We similarly describe findings from large head and neck cancer studies that have identified sets of susceptibility loci according to the histology or location of the cancers. Finally, we discuss future goals in integrating genetic and biomarker information for further streamlining risk assessment for lung cancer and identifying gaps and needs for risk assessment in smoking-related diseases. Citation Format: Christopher I. Amos, Laura Bierut, Margaret R. Spitz, James McKay. Role of environment in genetic predisposition: Lessons from tobacco studies [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA15.