Germline Mutations as Risk Factors for Lung Cancer: A Systematic Review and Meta-Analysis.

Inherited predispositions to lung cancer are increasingly recognized, but the prevalence and distribution of pathogenic germline variants (PGVs) remain incompletely characterized. We performed a systematic literature review of studies reporting the prevalence of pathogenic or likely pathogenic (P/LP) germline variants in patients with lung cancer. Random-effects models pooled overall prevalence estimates and gene-specific frequencies for frequently reported genes (EGFR, BRCA1, BRCA2, ATM, CHEK2, and TP53). Subgroup analyses were performed according to cohort type and ancestry. Univariable meta-regression was used to evaluate associations between mean age and sequencing panel size with P/LP prevalence. Case reports and series were qualitatively summarized. A total of 28 studies were included in the meta-analysis. The pooled prevalence of P/LP PGVs was 7.9% (95% confidence interval: 3.8%-15.9%) with high heterogeneity (I2 = 98.8%). Gene-specific prevalence rates were as follows: BRCA2, 0.96%; ATM, 0.67%; TP53, 0.57%; CHEK2, 0.49%; BRCA1, 0.48%; and EGFR, 0.17%. The high-risk enriched cohort had a higher prevalence of P/LP PGVs, whereas variants in DNA damage repair genes were more frequent in non-Asian populations than in East Asians (p < 0.05). A higher PGV prevalence was associated with a lower study-level mean age (per-year odds ratio = 0.91 for increasing age; p = 0.024) and larger sequencing panels (per log increase in tested genes, odds ratio = 1.72; p = 0.013). Case reports described more than 15 rare PGVs, most frequently involving EGFR, particularly EGFR T790M. Approximately 8% of patients with lung cancer harbor P/LP germline variants, most commonly in DNA damage repair genes. A younger study-level mean age was associated with higher overall prevalence, whereas variants in several DNA damage repair genes were more frequent in non-Asian or mixed populations than in East Asian populations, supporting risk-adapted genetic evaluation.