Enrichment of SMARCA4 mutations in lung carcinomas presenting as cancer of unknown primary

Identifying the primary tumor in cancer of unknown primary (CUP) remains a major clinical challenge. While WGS-based tissue-of-origin (TOO) prediction has improved diagnostic precision, its use is constrained by cost and availability. We investigated whether a low-complexity surrogate, combining SMARCA4 mutations and smoking history, can identify a lung cancer origin in CUP (CUP-Lung).

We retrospectively identified 305 provisional CUP cases from two Dutch CUP referral centers (2022-2025). Integration of whole-genome sequencing (WGS)-based TOO prediction with clinicopathological data identified 58 patients (18.9%) with CUP-Lung. Associations between SMARCA4 mutations, smoking history, and CUP-Lung were assessed using comparative and regression analyses.

SMARCA4 mutations were present in 36.2% of CUP-Lung cases, significantly higher than in the overall CUP cohort (10.7%) and TCGA lung cancer datasets (6-8%). CUP-Lung cases had higher tumor mutational burden (median 21.5 vs. 12.6 mut/Mb, p < 0.001) and enriched smoking-related mutational signatures (p < 0.001). Smoking history was reported in 87.9% of cases. Smoking history (OR 4.9, 95% CI 2.2-10.9, p < 0.001) and SMARCA4 mutation (OR 10.3, 95% CI 4.5-23.8, p < 0.001) independently predicted CUP-Lung, together conferring a 76.0% probability of lung origin. No statistical differences were found between cases with and without detectable pulmonary involvement.

Combined smoking history and SMARCA4 mutations support lung cancer classification even in the absence of detectable pulmonary involvement enabling organ-directed treatment when WGS is unavailable.