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

Area of Science:

• Genetics
• Oncology
• Bioinformatics

Background:

• Inherited predispositions to lung cancer are increasingly recognized.
• The prevalence and distribution of pathogenic germline variants (PGVs) in lung cancer patients are not fully understood.
• Understanding PGV prevalence is crucial for genetic evaluation and risk stratification.

Purpose of the Study:

• To systematically review and meta-analyze the prevalence of pathogenic or likely pathogenic (P/LP) germline variants in lung cancer patients.
• To determine gene-specific frequencies of commonly reported PGVs.
• To explore factors associated with PGV prevalence, including cohort type, ancestry, age, and sequencing panel size.

Main Methods:

• Systematic literature review of studies reporting P/LP germline variants in lung cancer.
• Random-effects meta-analysis to pool prevalence estimates and gene frequencies.
• Subgroup analyses by cohort type and ancestry; meta-regression for age and panel size.

Main Results:

• Pooled prevalence of P/LP PGVs was 7.9% across 28 studies, with high heterogeneity.
• Gene-specific prevalences: BRCA2 (0.96%), ATM (0.67%), TP53 (0.57%), CHEK2 (0.49%), BRCA1 (0.48%), EGFR (0.17%).
• Higher prevalence in high-risk cohorts; DNA damage repair gene variants more frequent in non-Asian populations. Younger age and larger panels associated with higher prevalence.

Conclusions:

• Around 8% of lung cancer patients harbor P/LP germline variants, predominantly in DNA damage repair genes.
• Prevalence is influenced by younger age and non-Asian ancestry.
• Findings inform genetic evaluation strategies for lung cancer patients.