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.

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.

UNASSIGNED: The multi-subunit SWI/SNF chromatin remodeling complex is a key epigenetic regulator for many cellular processes, and several subunits are found to be mutated in human cancers. The inactivating mutations of SMARCA4, the ATPase subunit of the complex, result in cellular dependency on the paralog SMARCA2 for survival. This observed synthetic lethal relationship posits targeting SMARCA2 in SMARCA4-deficient settings as an attractive therapeutic target in oncology.
UNASSIGNED: This review covers patent literature disclosed during the 2019-30 June 2023 period which claim ATPase inhibitors and PROTAC degraders that bind to the ATPase domain of SMARCA2 and/or SMARCA4. A total of 16 documents from 6 applicants are presented.
UNASSIGNED: The demonstration of cellular dependence on SMARCA2 ATPase activity in SMARCA4-deficient settings has prompted substantial research toward SMARCA2-targeting therapies. Although selectively targeting the ATPase domain of SMARCA2 is viewed as challenging, several ATPase inhibitor scaffolds have been disclosed within the last five years. Most early compounds are weakly selective, but these efforts have culminated in the first dual SMARCA2/SMARCA4 ATPase inhibitor to enter clinical trials. Data from the ongoing clinical trials, as well as continued advancement of SMARCA2-selective ATPase inhibitors, are anticipated to significantly impact the field of therapies, targeting SMARCA4-deficient tumors.

SMARCA4/BRG1 is a catalytic subunit of the SWItch/sucrose non-fermentable (SWI/SNF) complex and its inactivation is known to drive a variety of cancers across different organs. SMARCA4/BRG1-deficient carcinoma is a relatively new entity in the sinonasal region, and a comprehensive molecular investigation of the underlying genetic abnormalities is largely lacking. In this study, we report two new cases of SMARCA4/BRG1-deficient sinonasal carcinoma with targeted next-generation sequencing analysis, both of which revealed activating mutation of CTNNB1 in addition to somatic loss-of-function mutation of SMARCA4, providing further insights into its tumorigenesis and theoretical basis for the potential future targeted therapy. Activating CTNNB1 mutations in our cases may provide further evidence that SMARCA4-deficient sinonasal carcinoma, sinonasal teratocarcinosarcoma, and olfactory carcinoma are genetically closely related lesions, as recently proposed in the literature.

Coffin-Siris syndrome (CSS) is a rare neurodevelopmental and multisystemic disorder with wide genetic heterogeneity and phenotypic variability caused by pathogenic variants in the BAF complex with 341 cases enrolled in the CSS/BAF-related disorders registry by 2021. Pathogenic variants of ARID1A account for 7-8% of cases with CSS phenotype. Malignancy has been previously reported in six individuals with CSS associated with BAF mutations. Two of these malignancies including one acute lymphoid leukemia and one hepatoblastoma were reported in ARID1A-associated CSS (ARID1A-CSS). Alterations in ARID1A are among the most common molecular aberrations in human cancer. Somatic deletion of 1p and specifically of 1p36.11 containing ARID1A is frequently seen in hepatoblastoma and has been associated with high-risk features. Here we report a child with CSS Phenotype and a novel de novo variant of ARID1A with hepatoblastoma. Because hepatoblastoma has an incidence of 1 per million children, the presence of hepatoblastoma in 2 of 30 known cases of ARID1A-CSS is significant. ARID1A-CSS should be included among the cancer predisposition syndromes associated with an increased risk of hepatoblastoma and tumour surveillance considered for these patients. The role of ARID1A in the pathogenesis and outcome of hepatoblastoma deserves further investigation.

BACKGROUND: The association between SWI/SNF genomic alterations and responses to immune checkpoint inhibitors (ICIs) remains conflicting. This meta-analysis was performed to systematically assess the impact of SWI/SNF genomic alterations on response to ICIs in cancer.
METHODS: Relevant studies were searched in multiple databases updated to April 29, 2021. Outcomes of interest included prevalence of SWI/SNF alterations, overall survival (OS), progression-free survival (PFS) and time to treatment failure (TTF). For survival data, the hazard ratio (HR) was adopted, and the effect size was described as 95% confidence intervals (CI).
RESULTS: 15 studies involving 10,849 patients were included, with the overall frequency of 18.5% in SWI/SNF alterations. Across different cancer types, the mutational frequency of PBRM1 (32.0%) was the highest, followed by ARID1A (18.1%), SMARCA4 (15.6%), SMARCA2 (10.3%), ARID2 (8.1%), SMARCC2 (6.4%) and SMARCB1 (5.0%). Overall analysis showed that SWI/SNF alterations were not associated with improved OS (HR: 0.822, 95 %CI: 0.583-1.158, p = 0.262), PFS (HR: 0.608, 95 %CI: 0.434-1.067, p = 0.094) and TTF (HR: 0.923, 95 %CI: 0.757-1.125, p = 0.427) in patients treated with ICIs. In subgroup analysis, PBRM1 mutations were observed to be linked with improved OS (HR: 0.650, 95 %CI: 0.440-0.960, p = 0.030), PFS (HR: 0.539, 95 %CI: 0.314-0.926, p = 0.025) and TTF (HR: 0.490, 95 %CI: 0.271-0.885, p = 0.018) in RCC patients receiving ICIs.
CONCLUSIONS: The overall prevalence of SWI/SNF alterations was 18.5% across different cancer types. Except for PBRM1 mutations in RCC, SWI/SNF alterations may be uncorrelated with improved clinical outcomes in cancer.

Hepatocellular carcinoma (HCC) is a primary liver malignancy with a high global prevalence and a dismal prognosis. Studies are urgently needed to examine the molecular pathogenesis and biological characteristics of HCC. Chromatin remodelling, an integral component of the DNA damage response, protects against DNA damage-induced genome instability and tumorigenesis by triggering the signalling events that activate the interconnected DNA repair pathways. The SWI/SNF complexes are one of the most extensively investigated adenosine triphosphate-dependent chromatin remodelling complexes, and mutations in genes encoding SWI/SNF subunits are frequently observed in various human cancers, including HCC. The mutated SWI/SNF complex subunits exert dual functions by accelerating or inhibiting HCC initiation and progression. Furthermore, the abnormal SWI/SNF complexes influence the transcription of interferon-stimulated genes, as well as the differentiation, activation and recruitment of several immune cell types. In addition, they exhibit synergistic effects with immune checkpoint inhibitors in the treatment of diverse tumour types. Therefore, understanding the mutations and deficiencies of the SMI/SNF complexes, together with the associated functional mechanisms, may provide a novel strategy to treat HCC through targeting the related genes or modulating the tumour microenvironment.

SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity of thoracic sarcomas with an undifferentiated rhabdoid morphology and SMARCA4 inactivation. Regardless of some reports about the histopathological findings so far, there have been only a few reports about the cytological features. In this article, we present the pathological features of 2 SMARCA4-DTS cases, including the cytological findings. Histopathologically, the tumor cells showed atypical loosely cohesive large epithelioid cells focally with geographic necrosis. Some cells were characterized by rhabdoid cells. Both patients showed intrathoracic masses with a history of smoking, and loss of SMARCA4 expression was confirmed with histopathological specimens. Immunohistochemically, tumor cells of both cases were at least focally positive for cytokeratin, CD34, CD99, synaptophysin, SOX2, and SALL4. In addition, tumor cells demonstrated significantly reduced expression of BRG1/SMARCA4 and SMARCA2. In conclusion, SMARCA4-DTS should be taken into consideration in the differential diagnosis of tumors with undifferentiated rhabdoid morphology involving the thoracic region.

SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity with a poor prognosis that is defined by certain genetic alterations in the BAF chromatin remodeling complex, specifically SMARCA4 and SMARCA2. We present a case of a SMARCA4-DTS in a 59 year-old male with a heavy smoking history who was found to have an unexpected right upper lobe lung mass on routine chest radiograph after a visit to his primary care physician. This led to a biopsy with a diagnosis of poorly differentiated carcinoma at an outside institution. The patient was subsequently seen at our facility for surgical intervention. The right upper lobectomy contained a 7.2-cm poorly differentiated malignancy with slightly discohesive cells arranged in sheets and nests, abundant geographic necrosis, and with many areas showing rhabdoid morphology. The tumor was focally reactive for CK7, AE1/3, Cam5.2, and SALL4 and showed scattered reactivity for CD34 and SOX2. There was complete loss of reactivity for both SMARCA4 and SMARCA2. The histology and immunophenotype were all consistent with the diagnosis of a SMARCA4-DTS. Next-generation sequencing showed a frameshift mutation in the SMARCA4 gene and no abnormality with the SMARCA2 gene. Interestingly, this tumor was confined to the pulmonary parenchyma with no invasion of the visceral pleura nor the mediastinum and with no clinically apparent metastases at the time of presentation. This case is presented to add to the cohort of cases described to date and to discuss the immunohistochemical and molecular findings with regard to SMARCA2.