A novel oncogenic nonsense mutation of SMARCA4 and genetic characteristic analysis of SMARCA4 (BRG1)-deficient undifferentiated tumor of the bladder.

SMARCA4 (BRG1)-deficient undifferentiated tumor is a rare and highly aggressive malignant tumor. Cases arising in the bladder are exceedingly rare, and their molecular pathogenesis remains poorly understood. Here, we present the first, to our knowledge, report of a case of bladder SMARCA4 (BRG1)-deficient undifferentiated tumor incorporating comprehensive genomic profiling. Ultra-deep sequencing analysis using a 601-gene panel targeting tumor molecular targeted therapy, immunotherapy, and hereditary susceptibility revealed a novel oncogenic nonsense mutation in the SMARCA4 gene (p.K867*), with a high mutant allele frequency of 71%. This mutation has not been previously reported in any tumor type. Meanwhile, loss of heterozygosity was also found in the SMARCA4 gene. Additionally, seven variants with potential clinical significance-TP53 (c.919 + 1G > A), TP53 (c.823dup), FGF19 amplification, FGF3 amplification, CCND1 amplification, FGF4 amplification, and STAG2 (c.289-2A > T)-and nine variants of uncertain clinical significance-BRIP1, EPHA3, FLT4, GLI1, KMT2C, KMT2D, LGMN, MGA, and RICTOR-were detected. This suggests that besides SMARCA4 deficiency, alterations in other genes may cooperatively contribute to the tumorigenesis of bladder undifferentiated tumors. These findings provide a reference for subsequent exploration of precise diagnostic and prognostic assessment and treatment strategies for this disease.