Genetic analysis of lung cancer reveals novel susceptibility loci and germline impact on somatic mutation burden

Large international efforts are describing how germline variants influence susceptibility to lung cancer. We have undertaken a genome-wide association by proxy (GWAx) study of lung cancer in 48,843 proxy ''cases'' with a parent/sibling with lung cancer to 195,387 proxy controls without a family history of any cancer from the UK Biobank and meta-analysed the results with previously described GWA study results. 21 loci achieved genome-wide statistical significance, including 8 novel loci including expression quantitative trait loci (eQTLs) in DNA repair genes (CHEK1, MDM4) and metabolic genes (CYP1A1). This study also discovered loci associated with propensity to smoke, such as both subunits of a key element in nicotine response, the neuronal 4{beta}2 nicotinic acetylcholine receptor. Polygenic risk scores (PRS) analysis of variants below genome-wide significant threshold in an independent lung cancer population demonstrated that variants related to eQTLs and/or smoking propensity are enriched for susceptibility variants. PRS of lung cancer variants related to propensity to smoke were associated with somatic mutation burden in matched tumours from the same patients, with individuals with higher polygenic genetic risk having increased mutation burden in two case cohorts. This study has expanded the number of susceptibility loci linked with lung cancer and provided insights into how the molecular mechanisms by which these susceptibility variants contribute to the development of lung cancer.