Illustrating the “Quiet Genome” Concept of SMARCA4-Deficient Uterine Sarcoma Via Whole-Exome Sequencing: A Highly Aggressive Case in a Young Woman

SMARCA4- deficient undifferentiated uterine sarcoma (SDUS) is a rare, highly aggressive SWI/SNF-deficient malignancy that can morphologically overlap with undifferentiated endometrial carcinoma (UDEC). Although prior targeted sequencing studies have suggested that SDUS often has a "quiet genome," exome-wide corroboration remains limited. We report a 23-yr-old woman who presented with a >15 cm uterine mass and underwent hysterectomy with bilateral salpingo-oophorectomy, followed by rapid peritoneal dissemination and para-aortic metastases within 2 mo. The disease was refractory to gemcitabine/docetaxel and the patient died 6 mo postoperatively. Histologically, the tumor consisted of sheets of monomorphic undifferentiated epithelioid cells with rhabdoid features, focal phyllodes-like architecture entrapping benign endometrial glands and stromal hyalinization, and no identifiable carcinomatous component. Immunohistochemistry demonstrated complete loss of SMARCA4 (BRG1) and SMARCA2 (BRM) with retained SMARCB1 (INI1), a wild-type p53 pattern, intact mismatch repair protein expression, and negativity for claudin-4 and SOX2. Whole-exome sequencing with copy-number analysis of paired tumor and nontumor tissue identified biallelic SMARCA4 inactivation (somatic frameshift deletion c.3717del, p.W1239fs; VAF 0.89) with loss of heterozygosity at 19p13.2, microsatellite stability, and low tumor mutational burden (0.70 mut/Mb), without additional canonical driver mutations; notably, no TP53 mutation was detected despite hemizygous 17p loss. A focal copy-number gain involving the BRCA1 locus was also identified; however, its biological significance remains uncertain. This case provides exome-wide support for the "quiet genome" concept in SDUS and underscores its biological distinction from UDEC. Comprehensive genomic profiling may assist diagnosis in this aggressive malignancy.