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

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. 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. 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. 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.