Systematic review and meta-analysis of studies of germline mutations as risk factors for lung cancer

Inherited predispositions to lung cancer are increasingly recognized, but the prevalence and distribution of pathogenic germline variants are incompetely characterized. Systematic review and meta-analysis investigated the prevalence of pathogenic or likely pathogenic (P/LP) germline variants in lung cancer patients. Twenty-eight studies were included. The pooled prevalence of P/LP germline variants was 7.9% (95% CI 3.8-15.9) with high heterogeneity (I²=98.8%). Prevalence rates of commonly reported genes were 0.96% for BRCA2, 0.67% for ATM, 0.57% for TP53, 0.49% for CHEK2, 0.48% for BRCA1, and 0.17% for EGFR. The high-risk enriched cohort had a higher prevalence of P/LP germline variants, while variant in DNA damage repair genes were more frequent in non-Asian populations than in East Asians (p<0.05). Higher P/LP germline variant prevalence was associated with lower study-level mean age (for increasing age per year OR 0.91; p=0.024) and larger sequencing panel (per log increase in tested genes OR 1.72; p=0.013). The authors conclude that approximately 8% of lung cancer patients harbor P/LP germline variants, with the highest frequencies in DNA damage repair genes.