Lung cancer has long been framed as a smoker's disease, yet a meaningful fraction of cases — roughly one in six — arise in people who never touched a cigarette. This systematic review reframes that gap, pointing to inherited mutations in DNA-damage repair pathways as a plausible biological explanation that also carries direct implications for screening, targeted treatment, and family risk counseling.
Drawing on 39 studies culled from nearly 5,700 screened publications and following PRISMA methodology, the review maps the germline mutation landscape across NSCLC subtypes. The most frequently implicated genes — ATM, BRCA1/2, PALB2, CHEK2, TP53, and EGFR — are largely the same genes associated with hereditary breast, ovarian, and pancreatic cancers, suggesting shared cancer-predisposition architecture across tissue types. Prevalence estimates varied substantially by gene, ethnicity, tumor histology, and cohort design, but certain variants clustered disproportionately in younger patients and adenocarcinoma cases. Critically, some germline variants appeared to predict differential sensitivity or resistance to existing targeted therapies, raising the possibility that germline status could influence treatment selection independently of somatic tumor profiling.
This finding lands in a research climate already grappling with the underutilization of germline testing in thoracic oncology. Unlike breast or colorectal cancer, where hereditary testing is now standard of care, NSCLC germline screening remains largely opportunistic. The review's signal that DNA-repair gene carriers may respond differently to PARP inhibitors and other targeted agents aligns with early clinical trial data but remains observational in most cases — a key limitation. Cohort heterogeneity across the 39 included studies also complicates direct prevalence comparisons. Nonetheless, this is a confirmatory and increasingly actionable body of evidence. For never-smoker adenocarcinoma patients especially, germline testing appears warranted not just for prognostic clarity, but because first-degree relatives of carriers may themselves carry elevated lung cancer risk with no current pathway to early detection.