Association Between Rare Germline Variants in Cancer Susceptibility Genes and Lung Cancer Risk.

Few germline susceptibility genes have been well established for lung cancer. We aimed to evaluate associations between germline variants in known hereditary cancer genes and lung cancer risk. We analyzed subjects of European ancestry from two datasets: 2,272 LC cases and 185,510 controls from the UK Biobank, and 824 LC cases from Rush University Medical Center (RUSH) with 56,878 population controls from the Genome Aggregation Database (gnomAD). Rare pathogenic germline variants in 123 ClinGen-curated hereditary cancer genes were first tested for lung cancer risk in the UK Biobank using gene-based burden testing (robust SKAT-O). Genes with suggestive associations were further evaluated in the RUSH/gnomAD dataset. Meta-analysis of the two datasets was performed to estimate overall evidence and pooled odds ratios. Rare germline variants in ten genes showed nominally significant associations with lung cancer in the UK Biobank (p<0.05), and TP53 showed a borderline signal (p=0.11). These genes were tested in the RUSH/gnomAD dataset, and meta-analysis identified suggestive evidence supporting eight genes associated with increased lung cancer risk (p<0.05), including three previously reported lung cancer genes (ATM, BRCA2, TP53) and five novel genes (RB1, MET, CYLD, PDGFRA, CTNNA1). In the UK Biobank incident lung cancer cohort, aggregated rare pathogenic variants in these eight genes were significantly associated with lung cancer risk and earlier age at lung cancer diagnosis, independent and complementary to smoking history at recruitment. Suggestive evidence supporting associations between rare germline variants in eight hereditary cancer genes and lung cancer were obtained from two large independent datasets.