For the roughly one in six lung cancer patients who never smoked, the question of why they developed the disease has long lacked a satisfying answer. A new systematic review consolidates emerging evidence that inherited, rather than tobacco-acquired, mutations in key tumor-suppressor and DNA-integrity genes meaningfully contribute to non-small cell lung cancer susceptibility — a finding with direct consequences for how families and clinicians should approach genetic screening.
Drawing on 39 studies selected from a pool of 5,687 screened publications and following PRISMA methodology with PROSPERO pre-registration, the review maps the landscape of pathogenic germline variants in NSCLC. The implicated genes cluster around DNA damage response and cell cycle control pathways: ATM, BRCA1/2, PALB2, CHEK2, TP53, and EGFR emerged as the most consistently identified drivers. Importantly, certain variants showed disproportionate association with lung adenocarcinoma in younger patients and never-smokers — a histological and demographic profile that differs markedly from the smoking-associated squamous cell pattern. Some variants also correlated with differential sensitivity or resistance to existing targeted therapies, adding a pharmacogenomic dimension beyond mere risk stratification.
This review is most valuable for reframing NSCLC within a hereditary cancer framework that clinicians have historically reserved for breast, ovarian, or colorectal malignancies. The genes flagged here — particularly BRCA1/2 and PALB2 — are already actionable in other tumor contexts, and PARP inhibitor sensitivity data from those cancers may inform future NSCLC trial design. However, critical limitations temper clinical translation: germline variants remain rare in aggregate NSCLC populations, prevalence estimates vary substantially by ethnicity and cohort composition, and causal inference from predominantly observational data is constrained. The review is also heterogeneous across its 39 included studies, making pooled effect estimates unreliable. Taken as a body, the evidence is confirmatory and directionally useful rather than paradigm-shifting, but it builds a credible case for expanding germline testing panels in younger, never-smoker NSCLC patients — and for extending genetic counseling conversations to their first-degree relatives.