LAUSR

Background Individual susceptibility to carcinogens may depend on genetic background. We performed for the first-time Whole Exome Sequencing (WES) of germline DNA from individuals presenting phenotypes of extreme sensitivity and resistance to developing tobacco-induced lung adenocarcinoma, in order to characterize the genetic background associated with these relevant phenotypes. Methods We performed WES of germline DNA from heavy smokers (≥15 pack-years) who either developed lung adenocarcinoma at an early age (≤55 years, extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (≥72 years, extreme controls, n=50). We selected non-synonymous variants (missense and non-sense) located in the coding regions and consensus splice sites of the genes showing significantly different allelic frequencies between both cohorts. We validated our results in germline data from 52 additional extreme cases selected from TCGA using the same criteria (diagnosis of lung adenocarcinoma at ≤55 years, tobacco consumption ≥15 pack-years). Results The mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.5 and 54.4 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 107 of these in 52 extreme cases selected from TCGA (mean age 49.3 years, mean tobacco consumption 37 pack-years). Nine validated variants, located in relevant cancer related genes, such as PARP4 (DNA repair), HLA-A (antigen presentation) or NQO1 (detoxification) among others, achieved statistical significance in the False Discovery Rate test (FDR) (table 1). The most significant validated variant (p=4.48 × 10-5) was located in the tumor-suppressor gene ALPK2. The Reactome Pathway Database analysis showed that the genes harboring the most significant validated variants were significantly related to antigen processing and presentation, interferon and cytokine signaling and immune regulation, also achieving statistical significance in the FDR test (table 2). Conclusions We describe for the first time genetic variants associated with extreme phenotypes of high and low-risk for the development of tobacco-induced lung adenocarcinoma, assessed with WES. The most significant validated variants were related with antigen presentation, immune regulation and DNA repair. Our results and our strategy warrant further development to characterize these clinically relevant phenotypes. Ethics Approval The study was approved by the Investigational Review Board of Clinica Universidad de Navarra, approval number 021/2009.