Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial cancer.

OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. CONCLUSION: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.

SWI/SNF Complex Connects Signaling and Epigenetic State in Cells of Nervous System.

SWI/SNF protein complexes are evolutionarily conserved epigenetic regulators described in all eukaryotes. In metameric animals, the complexes are involved in all processes occurring in the nervous system, from neurogenesis to higher brain functions. On the one hand, the range of roles is wide because the SWI/SNF complexes act universally by mobilizing the nucleosomes in a chromatin template at multiple loci throughout the genome. On the other hand, the complexes mediate the action of multiple signaling pathways that control most aspects of neural tissue development and function. The issues are discussed to provide insight into the molecular basis of the multifaceted role of SWI/SNFs in cell cycle regulation, DNA repair, activation of immediate-early genes, neurogenesis, and brain and connectome formation. An overview is additionally provided for the molecular basis of nervous system pathologies associated with the SWI/SNF complexes and their contribution to neuroinflammation and neurodegeneration. Finally, we discuss the idea that SWI/SNFs act as an integration platform to connect multiple signaling and genetic programs.

SMARCB1/INI1-deficient undifferentiated tumour of the thorax: a case report and review of the literature.

The 5th WHO classification of thoracic tumours includes thoracic SMARCA4-deficient undifferentiated tumour (SMARCA4-UT) among the "other epithelial tumours of the lung" chapter. Herein, we present a case of undifferentiated thoracic neoplasm with retention of SMARCA4 expression, lack of NUT fusion protein and loss of SMARCB1/INI1 expression. After presenting the clinical and pathological features of the tumour, we carried out a review of the literature on the same topic. Albeit very rare, we believe this entity should be included in the heterogeneous group of undifferentiated neoplasms of the thorax.

SWI/SNF chromatin remodeling factor BAF60b restrains inflammatory diseases by affecting regulatory T cell migration.

Regulatory T (Treg) cells play a critical regulatory role in the immune system by suppressing excessive immune responses and maintaining immune balance. The effective migration of Treg cells is crucial for controlling the development and progression of inflammatory diseases. However, the mechanisms responsible for directing Treg cells into the inflammatory tissue remain incompletely elucidated. In this study, we identified BAF60b, a subunit of switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes, as a positive regulator of Treg cell migration that inhibits the progression of inflammation in experimental autoimmune encephalomyelitis (EAE) and colitis animal models. Mechanistically, transcriptome and genome-wide chromatin-landscaped analyses demonstrated that BAF60b interacts with the transcription factor RUNX1 to promote the expression of CCR9 on Treg cells, which in turn affects their ability to migrate to inflammatory tissues. Our work provides insights into the essential role of BAF60b in regulating Treg cell migration and its impact on inflammatory diseases.

Characterization of the SWI/SNF complex and nucleosome organization in sorghum.

The switch defective/sucrose non-fermentable (SWI/SNF) multisubunit complex plays an important role in the regulation of gene expression by remodeling chromatin structure. Three SWI/SNF complexes have been identified in Arabidopsis including BAS, SAS, and MAS. Many subunits of these complexes are involved in controlling plant development and stress response. However, the function of these complexes has hardly been studied in other plant species. In this study, we identified the subunits of the SWI/SNF complex in sorghum and analyzed their evolutionary relationships in six grass species. The grass species conserved all the subunits as in Arabidopsis, but gene duplication occurred diversely in different species. Expression pattern analysis in sorghum (Sorghum bicolor) showed that most of the subunit-encoding genes were expressed constitutively, although the expression level was different. Transactivation assays revealed that SbAN3, SbGIF3, and SbSWI3B possessed transactivation activity, which suggests that they may interact with the pre-initiation complex (PIC) to activate transcription. We chose 12 subunits in sorghum to investigate their interaction relationship by yeast two-hybrid assay. We found that these subunits displayed distinct interaction patterns compared to their homologs in Arabidopsis and rice. This suggests that different SWI/SNF complexes may be formed in sorghum to perform chromatin remodeling functions. Through the integrated analysis of MNase-seq and RNA-seq data, we uncovered a positive relationship between gene expression levels and nucleosome phasing. Furthermore, we found differential global nucleosome enrichments between leaves and roots, as well as in response to PEG treatment, suggesting that dynamics of nucleosome occupancy, which is probably mediated by the SWI/SNF complex, may play important roles in sorghum development and stress response.

Outcomes of SWI/SNF complex-deficient sinonasal carcinomas in a Southeast Asian cohort.

BACKGROUND: SWI/SNF complex-deficient sinonasal carcinomas are rare, genetically distinct, and aggressive entities. METHODS: SMARCB1 and SMARCA4 immunohistochemistry was retrospectively performed on a cohort of undifferentiated, poorly differentiated, and poorly defined sinonasal carcinomas. Survival outcomes were compared between SMARCB1/SMARCA4 (SWI/SNF complex)-deficient and -retained groups. RESULTS: Eight SWI/SNF complex-deficient (six SMARCB1-deficient, two SMARCA4-deficient) cases were identified among 47 patients over 12 years. Triple-modality treatment was more frequently utilized in SWI/SNF complex-deficient carcinomas than in SWI/SNF complex-retained carcinomas (71.4% vs. 11.8%, p = 0.001). After a median follow-up of 21.3 (IQR 9.9-56.0) months, SWI/SNF complex-deficient sinonasal carcinomas showed comparable recurrence rates (57.1% vs. 52.9%, p = 0.839), time-to-recurrence (7.3 [IQR 6.6-8.3] vs. 9.1 [IQR 3.9-17.4] months, p = 0.531), and overall survival (17.7 [IQR 11.8-67.0] vs. 21.6 [IQR 8.9-56.0] months, p = 0.835) compared to SWI/SNF complex-retained sinonasal carcinomas. CONCLUSION: Triple-modality treatment may improve survival in SWI/SNF complex-deficient sinonasal carcinomas.

The SWI/SNF chromatin remodelling complex regulates pancreatic endocrine cell expansion and differentiation in mice in vivo.

AIMS/HYPOTHESIS: Strategies to augment functional beta cell mass include directed differentiation of stem cells towards a beta cell fate, which requires extensive knowledge of transcriptional programs governing endocrine progenitor cell differentiation in vivo. We aimed to study the contributions of the Brahma-related gene-1 (BRG1) and Brahma (BRM) ATPase subunits of the SWI/SNF chromatin remodelling complex to endocrine cell development. METHODS: We generated mice with endocrine progenitor-specific Neurog3-Cre BRG1 removal in the presence of heterozygous (Brg1Δendo;Brm+/-) or homozygous (double knockout: DKOΔendo) BRM deficiency. Whole-body metabolic phenotyping, islet function characterisation, islet quantitative PCR and histological characterisation were performed on animals and tissues postnatally. To test the mechanistic actions of SWI/SNF in controlling gene expression during endocrine cell development, single-cell RNA-seq was performed on flow-sorted endocrine-committed cells from embryonic day 15.5 control and mutant embryos. RESULTS: Brg1Δendo;Brm+/- mice exhibit severe glucose intolerance, hyperglycaemia and hypoinsulinaemia, resulting, in part, from reduced islet number; diminished alpha, beta and delta cell mass; compromised islet insulin secretion; and altered islet gene expression programs, including reductions in MAFA and urocortin 3 (UCN3). DKOΔendo mice were not recovered at weaning; however, postnatal day 6 DKOΔendo mice were severely hyperglycaemic with reduced serum insulin levels and beta cell area. Single-cell RNA-seq of embryonic day 15.5 lineage-labelled cells revealed endocrine progenitor, alpha and beta cell populations from SWI/SNF mutants have reduced expression of Mafa, Gcg, Ins1 and Ins2, suggesting limited differentiation capacity. Reduced Neurog3 transcripts were discovered in DKOΔendo endocrine progenitor clusters, and the proliferative capacity of neurogenin 3 (NEUROG3)+ cells was reduced in Brg1Δendo;Brm+/- and DKOΔendo mutants. CONCLUSIONS/INTERPRETATION: Loss of BRG1 from developing endocrine progenitor cells has a severe postnatal impact on glucose homeostasis, and loss of both subunits impedes animal survival, with both groups exhibiting alterations in hormone transcripts embryonically. Taken together, these data highlight the critical role SWI/SNF plays in governing gene expression programs essential for endocrine cell development and expansion. DATA AVAILABILITY: Raw and processed data for scRNA-seq have been deposited into the NCBI Gene Expression Omnibus (GEO) database under the accession number GSE248369.

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

SWI/SNF family mutations in advanced NSCLC: genetic characteristics and immune checkpoint inhibitors' therapeutic implication.

BACKGROUND: SWItch/Sucrose NonFermentable (SWI/SNF) mutations have garnered increasing attention because of their association with unfavorable prognosis. However, the genetic landscape of SWI/SNF family mutations in Chinese non-small-cell lung cancer (NSCLC) is poorly understood. In addition, the optimal treatment strategy has not yet been determined. PATIENTS AND METHODS: We collected sequencing data on 2027 lung tumor samples from multiple centers in China to comprehensively analyze the genomic characteristics of the SWI/SNF family within the Chinese NSCLC population. Meanwhile, 519 patients with NSCLC from Sun Yat-sen University Cancer Center were enrolled to investigate the potential implications of immunotherapy on patients with SWI/SNF mutations and to identify beneficial subpopulations. We also validated our findings in multiple publicly available cohorts. RESULTS: Approximately 15% of Chinese patients with lung cancer harbored mutations in the SWI/SNF chromatin remodeling complex, which were mutually exclusive to the EGFR mutations. Patients with SWI/SNFmut NSCLC who received first-line chemoimmunotherapy had better survival outcomes than those who received chemotherapy alone (median progression-free survival: 8.70 versus 6.93 months; P = 0.028). This finding was also confirmed by external validation using the POPLAR/OAK cohort. SWI/SNFmut NSCLC is frequently characterized by high tumor mutational burden and concurrent TP53 or STK11/KEAP mutations. Further analysis indicated that TP53 and STK11/KEAP1 mutations could be stratifying factors in facilitating personalized immunotherapy and guiding patient selection. CONCLUSIONS: This study provides a step forward in understanding the genetic and immunological characterization of SWI/SNF genetic alterations. Moreover, our study reveals substantial benefits of immunotherapy over chemotherapy for SWI/SNF-mutant patients, especially the SWI/SNFmut and TP53mut subgroups.

Superficial CD34+ fibroblastic tumor with focal atypical presentation: A case report.

Superficial CD34+ fibroblastic tumors (SCPFTs) are rare mesenchymal tumors with distinct morphological features. Although several cases of SCPFT have been reported, a comprehensive understanding of its clinical and biological features necessitates the inclusion of additional cases. The current study presents a case of SCPFT, where morphological observations, immunohistochemical staining and fluorescence in situ hybridization (FISH) were performed. Immunohistochemistry revealed diffuse CD34 expression and integrase interactor 1 expression, whilst FISH indicated rearrangement of the PR/SET domain 10 gene. Microscopic assessment demonstrated typical SCPFT pathology, with a focal nodular region showing a high Ki-67 index, suggesting heterogeneity and the potential for local recurrence. The present study also briefly reviews the differential diagnosis of tumors with morphological similarities. It was found that the precise diagnosis of SCPFT relies on the distinctive pathological features, the use of immunohistochemical markers, including CD34 staining, and the differentiation from similar histological lesions.

Epigenetics.

Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities.

ARID1A Mutations in Gastric Cancer: A Review with Focus on Clinicopathological Features, Molecular Background and Diagnostic Interpretation.

AT-rich interaction domain 1 (ARID1A) is a pivotal gene with a significant role in gastrointestinal tumors which encodes a protein referred to as BAF250a or SMARCF1, an integral component of the SWI/SNF (SWItch/sucrose non-fermentable) chromatin remodeling complex. This complex is instrumental in regulating gene expression by modifying the structure of chromatin to affect the accessibility of DNA. Mutations in ARID1A have been identified in various gastrointestinal cancers, including colorectal, gastric, and pancreatic cancers. These mutations have the potential to disrupt normal SWI/SNF complex function, resulting in aberrant gene expression and potentially contributing to the initiation and progression of these malignancies. ARID1A mutations are relatively common in gastric cancer, particularly in specific adenocarcinoma subtypes. Moreover, such mutations are more frequently observed in specific molecular subtypes, such as microsatellite stable (MSS) cancers and those with a diffuse histological subtype. Understanding the presence and implications of ARID1A mutations in GC is of paramount importance for tailoring personalized treatment strategies and assessing prognosis, particularly given their potential in predicting patient response to novel treatment strategies including immunotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors.

Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes.

Macrophages elicit immune responses to pathogens through induction of inflammatory genes. Here, we examined the role of three variants of the SWI/SNF nucleosome remodeling complex-cBAF, ncBAF, and PBAF-in the macrophage response to bacterial endotoxin (lipid A). All three SWI/SNF variants were prebound in macrophages and retargeted to genomic sites undergoing changes in chromatin accessibility following stimulation. Cooperative binding of all three variants associated with de novo chromatin opening and latent enhancer activation. Isolated binding of ncBAF and PBAF, in contrast, associated with activation and repression of active enhancers, respectively. Chemical and genetic perturbations of variant-specific subunits revealed pathway-specific regulation in the activation of lipid A response genes, corresponding to requirement for cBAF and ncBAF in inflammatory and interferon-stimulated gene (ISG) activation, respectively, consistent with differential engagement of SWI/SNF variants by signal-responsive transcription factors. Thus, functional diversity among SWI/SNF variants enables increased regulatory control of innate immune transcriptional programs, with potential for specific therapeutic targeting.

SMARCC2 silencing suppresses oncogenic activation through modulation of chromatin accessibility in breast cancer.

SWI/SNF chromatin remodeling complexes play a key role in gene transcription as epigenetic regulators and are typically considered to act as tumor suppressors in cancers. Compared to other cancer-related components of the SWI/SNF complex, research on SMARCC2, a component of the initial BAF core, has been relatively limited. This study aimed to elucidate the role of SMARCC2 in breast cancer by employing various in vitro and in vivo methods including cell proliferation assays, mammosphere formation, and xenograft models, complemented by RNA-seq, ATAC-seq, and ChIP analyses. The results showed that SMARCC2 silencing surprisingly led to the suppression of breast tumorigenesis, indicating a pro-tumorigenic function for SMARCC2 in breast cancer, which contrasts with the roles of other SWI/SNF subunits. In addition, SMARCC2 depletion reduces cancer stem cell features of breast cancer cells. Mechanistic study showed that SMARCC2 silencing downregulated the oncogenic Ras-PI3K signaling pathway, likely by directly regulating the chromatin accessibility of the enhancers of the key genes such as PIK3CB. Together, these results expand our understanding of the SWI/SNF complex's role in cancer development and identify SMARCC2 as a promising new target for breast cancer therapies.

IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptional networks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities, integrating functional genomics screening, spatial proteomics, and global chromatin mapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is required for IRF4 expression and functionally associates with IRF4 protein on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitors remain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinations of SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providing a promising strategy for relapsed/refractory disease.

Unlocking cellular plasticity: Enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation.

The transformation from a fibroblast mesenchymal cell state to an epithelial-like state is critical for Induced Pluripotent Stem Cell (iPSC) reprogramming. In this report, we describe studies with PFI-3, a small molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunits of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings reveal that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition (MET) during iPSC formation. This transition is characterized by the upregulation of E-cadherin expression, a key protein involved in epithelial cell adhesion. Additionally, we identified COL11A1 as a reprogramming barrier and demonstrated COL11A1 knockdown increased reprogramming efficiency. Notably, we found that PFI-3 significantly reduced the expression of numerous extracellular matrix (ECM) genes, particularly those involved in collagen assembly. Our research provides key insights into the early stages of iPSC reprogramming, highlighting the crucial role of ECM changes and cellular plasticity in this process.

Muscle-specific pyruvate kinase isoforms, PKM1 and PKM2, regulate mammalian SWI/SNF proteins and histone 3 phosphorylation during myoblast differentiation.

Pyruvate kinase is a glycolytic enzyme that converts phosphoenolpyruvate and ADP into pyruvate and ATP. There are two genes that encode pyruvate kinase in vertebrates; Pkm and Pkl encode muscle- and liver/erythrocyte-specific forms, respectively. Each gene encodes two isoenzymes due to alternative splicing. Both muscle-specific enzymes, PKM1 and PKM2, function in glycolysis, but PKM2 also has been implicated in gene regulation due to its ability to phosphorylate histone 3 threonine 11 (H3T11) in cancer cells. Here, we examined the roles of PKM1 and PKM2 during myoblast differentiation. RNA-seq analysis revealed that PKM2 promotes the expression of Dpf2/Baf45d and Baf250a/Arid1A. DPF2 and BAF250a are subunits that identify a specific sub-family of the mammalian SWI/SNF (mSWI/SNF) of chromatin remodeling enzymes that is required for the activation of myogenic gene expression during differentiation. PKM2 also mediated the incorporation of DPF2 and BAF250a into the regulatory sequences controlling myogenic gene expression. PKM1 did not affect expression but was required for nuclear localization of DPF2. Additionally, PKM2 was required not only for the incorporation of phosphorylated H3T11 in myogenic promoters but also for the incorporation of phosphorylated H3T6 and H3T45 at myogenic promoters via regulation of AKT and protein kinase C isoforms that phosphorylate those amino acids. Our results identify multiple unique roles for PKM2 and a novel function for PKM1 in gene expression and chromatin regulation during myoblast differentiation.

Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.

The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers and innovative combination therapies can be used to address challenging and difficult to treat disease states. This review highlights key mechanisms that epigenetic writers, erasers, readers, and remodelers control, as well as their connection with disease states and recent advances in associated epigenetic therapies.

Gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT): a clinicopathological analysis of four rare cases.

BACKGROUND: SMARCA4, as one of the subunits of the SWI/SNF chromatin remodeling complex, drives SMARCA4-deficient tumors. Gastric SMARCA4-deficient tumors may include gastric SMARCA4-deficient carcinoma and gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Gastric SMARCA4-UT is rare and challenging to diagnose in clinical practice. The present report aims to provide insight into the clinicopathological characteristics and genetic alterations of gastric SMARCA4-UTs. RESULTS: We retrospectively reported four rare cases of gastric SMARCA4-UTs. All four cases were male, aged between 61 and 82 years. These tumors presented as ulcerated and transmural masses with infiltration, staged as TNM IV in cases 1, 2 and 4, and TNM IIIA in case 3. Pathologically, four cases presented solid architecture with undifferentiated morphology. Cases 2 and 3 showed focal necrosis and focal rhabdoid morphology. Immunohistochemical staining showed negative expression of epithelial markers and deficient expression of SMARCA4. Furthermore, positivity for Syn (cases 1, 2 and 3) and SALL4 (cases 1 and 2) were observed. Mutant p53 expression occurred in four cases, resulting in strong and diffuse staining of p53 expression in cases 1, 2 and 4, and complete loss in case 3. The Ki67 proliferative index exceeded 80%. 25% (1/4, case 4) of cases had mismatch repair deficiency (dMMR). Two available cases (cases 1 and 3) were detected with SMRACA4 gene alterations. The response to neoadjuvant therapy was ineffective in case 1. CONCLUSIONS: Gastric SMARCA4-UT is a rare entity of gastric cancer with a poor prognosis, predominantly occurs in male patients. The tumors are typically diagnosed at advanced stages and shows a solid architecture with undifferentiated morphology. Negative expression of epithelial markers and complete loss of SMARCA4 immunoexpression are emerging as a useful diagnostic tool for rare gastric SMARCA4-UTs.