SMARCA4 ‐deficient undifferentiated malignancies in the digestive system: clinicopathological features and prognostic significance with genomic insights from the TCGA cohort

Deficiency in SWItch/Sucrose Non-FermenTable (SWI/SNF) related barrier-to-autointegration factor (BAF) chromatin remodeling complex subunit ATPase 4 (SMARCA4) drives aggressive behavior across various undifferentiated malignancies. However, its clinicopathological features, prognostic analysis, and molecular significance in undifferentiated digestive system malignancies, clinically rare and poorly characterized entities, remain incompletely elucidated. This study investigated the clinicopathological characteristics and prognostic significance of a retrospective cohort (n = 43). Immunohistochemistry (IHC) identified SMARCA4 deficiency in 30.2% of undifferentiated malignant tumors of the digestive system. Clinically, SMARCA4 deficiency constituted a significant poor-prognosis predictor, correlating with poorer overall survival [OS; hazard ratio (HR) = 3.054, 95% confidence interval (CI) 1.277-7.306, log-rank p = 0.006] and disease-free survival (DFS; HR = 2.717, 95% CI 1.129-6.539, log-rank p = 0.015), independent of assessed lineage markers or microsatellite status. Integrated analysis of The Cancer Genome Atlas (TCGA) data of digestive system malignancies revealed that SMARCA4-mutated tumors exhibited elevated tumor mutational burden (TMB) and distinct co-mutation patterns. Notably, SMARCA4 mutations significantly co-occurred with multiple potentially actionable therapeutic targets, including receptor tyrosine kinases (ERBB2, ERBB3, MET, and RET), DNA damage response genes (BRCA2), and mismatch repair genes (MLH1, MSH2, MSH6). Collectively, our findings identified SMARCA4 deficiency as a predictor of poor prognoses in digestive system malignancies, suggesting a distinct genomic context that may inform therapeutic stratification, including targeted and immunotherapeutic approaches, by focusing on these high-frequency co-mutated targets. © 2026 The Pathological Society of Great Britain and Ireland.