Background: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer. Methods: We studied clinical and tumor characteristics of germline PV in 5118 patients who underwent prospective genomic profiling using paired tumor-normal tissue samples in 468 cancer genes. Results: Germline PV in high/moderate penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n=54), CHEK2 (n=30) and ATM (n=26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared to non-carriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1 and MEN1) were diagnosed at younger age compared to non-carriers, and of tumor suppressors, 75% demonstrated bi-allelic inactivation in tumors. Significantly higher proportion of germline PV in high/moderate penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors or early age at diagnosis compared to unselected patients (10.5% vs 4.1%; p-value=1.7e-04). Conclusions: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer. Impact: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance.

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