Lung cancer in never-smokers has long been a clinical puzzle — one that inherited genetics may finally help unravel. A substantial proportion of non-small cell lung cancer cases arise in people with no meaningful tobacco history, and understanding why has direct implications for early screening, family risk counseling, and the selection of targeted therapies.
This PRISMA-compliant systematic review, drawing from 39 studies selected out of 5,687 screened, mapped the landscape of germline — meaning inherited, not acquired — mutations across NSCLC patients. The implicated genes cluster predominantly around DNA damage recognition and cell cycle regulation: ATM, BRCA1/2, TP53, PALB2, CHEK2, and EGFR all appear with meaningful frequency. Crucially, prevalence rates shifted considerably depending on cohort ethnicity, histological subtype, and smoking history, with younger patients and never-smokers disproportionately represented among germline mutation carriers. Specific variants were additionally associated with differential sensitivity or resistance to existing targeted therapies, opening a potential avenue for genotype-guided treatment selection.
This review arrives at an important moment. Germline testing in lung cancer has historically lagged far behind its use in breast or ovarian cancer, where BRCA-related risk is well-established in clinical guidelines. The overlap of implicated genes — particularly BRCA1/2 and PALB2 — suggests shared hereditary cancer syndromes may carry underappreciated pulmonary risk, especially in non-smokers. However, several caveats temper immediate clinical translation: germline mutations remain a minority driver of overall NSCLC burden, cohort sizes across the included studies varied considerably, and ascertainment bias toward high-risk or clinic-referred populations likely inflates observed prevalence estimates. The review is also inherently limited by the observational nature of its constituent studies, precluding causal inference. Still, the synthesis represents a meaningful step toward integrating germline profiling into routine NSCLC risk stratification — an area where the evidence base, while growing, remains immature relative to its clinical urgency.