Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma

Abstract

Background: Tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES).Methods: We performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). Results:The mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48×10 −5 ) was located in the tumor-suppressor gene ALPK2.Patiño-García et al. Extreme phenotypes of tobacco-induced lung cancer risk

Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma

“…We characterized with germline WES the genotype of individuals presenting extreme phenotypes of very high and very low risk of developing tobacco-associated lung adenocarcinoma and we validated our previous results from patients presenting similar phenotypes 6 ( Fig. 1 ).…”

“…The thresholds for age and tobacco consumption were those of our previous study 6 and were established empirically with the aim of selecting from our databases, including over 6600 subjects, those individuals presenting the most extreme phenotypes regarding the individual risk of developing tobacco-associated lung cancer. For this purpose, several combinations of different thresholds for age and tobacco consumption were tested, considering that while more extreme thresholds could define more extreme phenotypes, it would be at the expense of decreased sample size.…”

“…The discovery cohort was formed by 50 extreme cases and 50 extreme controls defined by virtually the same criteria for age and tobacco consumption. 6 There was no overlap between the individuals included in both cohorts.…”

“…We previously characterized with Whole Exome Sequencing (WES) the germline genetic profile of individuals presenting extreme phenotypes of very high and very low susceptibility to developing tobacco-associated lung adenocarcinoma, i.e.,: heavy smokers who either developed lung adenocarcinoma at a young age ( extreme cases , n = 50), or who did not develop lung cancer at an advanced age ( extreme controls , n = 50). 6 We limited the selection of extreme cases to lung adenocarcinoma to increase sample homogeneity. We observed significant differences among both groups in variants located in genes related to maintenance of genomic stability, regulation of inflammation, detoxification, transcriptional regulation, and HLA-mediated antigen presentation, among others.…”

Tumor Immune Microenvironment Related Gene-Based Model to Predict Prognosis and Response to Compounds in Ovarian Cancer

“…CTHRC1 modulates macrophage polarization to M2 phenotypes by directly binding to the TGF-β receptor II and TGF-β receptor III and activating TGF-β signaling ( 39 ). Aberrant expression of ALPK2 and CTHRC1 are independent high-risk factors for poor survival in multiple tumors ( 40 , 41 ). In this study, ALPK2, CPA3, and CTHRC1 were overexpressed in the patients at a late stage and associated with the debulking difficulty.…”