Beyond environmental risk: Genetic insights into lung cancer susceptibility through whole exome analysis

Background: unlike familial non polyposis colorectal cancer (Lynch syndrome) and familial breast cancer, no genes have been confidently associated with familial lung cancer with the exception of the EGFR and the TP53 genes. Germinal Pathogenetic Variants (GPV) in these two genes account for 0.34–0.9% and 0.8 % lung adenocarcinoma, respectively. Objective: the aim of this study was to identify rare genetic variants associated with higher risk of developing lung cancer. Methods: we performed exome sequencing in the germinal DNA of 16 patients who had a positive familial history of lung cancer: 14 patients had lung cancer at enrollment whereas 2 patients developed cancer during the course of the study. Two families had two affected relatives (mother and daughter and two sisters). Results: we identified rare clinically significant variants and VUS (Variant of Unknown Significance) in five well known cancer genes (POLE, PDGFRA, RTEL1, HNF1A and MITF) in five patients. One patient carried three variants and was exposed to environmental risk factors as smoking and asbestos. Common suscetibility variants in known cancer genes were also identified. We also identified additional potentially clinically relevant rare variants in other genes not previously associated to lung cancer. These genes include HGS, NME4, HAPLN1, ATMIN, CEACAM, MPEG1, USP4, TP53BP2, ERAP1, TNFAIP8L3, CASP1, MCC, SERPINA3, VIRMA, FOXK2, DNAH8, RASA2, GLI3. Conclusions: several lines of evidence suggest that these genes are of potential clinical impact in lung cancer even though they have not been correlated with lung cancer in the OMIM database or other genetic databases. Therefore, these genes deserve further investigations: segregation analysis, enlarged cohorts and in vitro/in vivo studies could help to clarify their role in lung cancer.