The role of germline mutations in non-small cell lung cancer. A systematic review of emerging genetic drivers and clinical implications

Background: Lung cancer is the second most common malignancy and the leading cause of cancer-related mortality worldwide. While tobacco exposure remains the main risk factor, 15-20% of cases occur in never-smokers, suggesting a role for genetic predisposition. Although infrequent compared to somatic alterations, germline alterations may contribute to non-small cell lung cancer (NSCLC) susceptibility, with implications for risk assessment, targeted therapy, and family counselling. Methods: A systematic review was conducted following PRISMA guidelines (PROSPERO ID:CRD420251081416). PubMed, SCOPUS, and Web of Science were searched up, for studies on germline mutations in NSCLC. Eligible articles reported prevalence, molecular characterization, or clinical relevance. Thirty-nine studies out of 5687 screened met inclusion criteria. Risk of bias was assessed using the Joanna Briggs Institute checklist. Results: Germline mutations result overall rare in NSCLC. Most germline mutations in NSCLC involve genes participating in DNA damage repair and cell cycle control, including ATM, BRCA1/2, TP53, PALB2, CHEK2, and EGFR. Prevalence rates varied by gene, cohort characteristics, ethnicity, and histology with specific variants linked to increased lung adenocarcinoma risk, often in younger or never-smoker patients. Certain variants may predict sensitivity or resistance to target therapies. Conclusions: Germline mutations constitute a minority of NSCLC cases but carry important prognostic, predictive, and preventive implications. Systematic germline testing in selected patients, particularly those with early-onset disease, strong family history, or tumor sequencing suggestive of hereditary variants, could guide precision oncology, enable targeted treatments, and facilitate familial risk management.