Hereditary Lung Cancer Risk: Recent Discoveries and Implications for Genetic Counseling and Testing

Abstract

Most lung cancer risk is attributed to environmental factors such as cigarette smoke. Family history also impacts lung cancer risk and as smoking rates decrease, the importance of understanding hereditary risk factors will increase. The goal of this paper is to review recent literature on germline variants that affect lung cancer risk, particularly in non-smokers. Germline EGFR T790M mutations have been identified in several families with a high density of lung cancer. Individuals with EGFR T790M appear to be predisposed to multifocal lung cancer and ground glass opacities. Other variants in EGFR (V769M, R776H, V843I), HER2 (G660D), and YAP1 (R331W) have also been identified in families with striking lung cancer histories. Several case reports have identified germline mutations in oncogenes as candidate high-risk lung cancer alleles. There are likely other germline lung cancer risk variants that have yet to be described. There are currently limited clinical testing options for these variants and limited guidance for medical management of carriers. More research with larger cohorts is needed to better understand hereditary lung cancer risks.