The mSWI/SNF chromatin remodeling complexes are critical regulators of genomic stability, particularly in their role in orchestrating DNA repair and modulating cellular responses to ionizing radiation therapy. Their involvement has positioned these molecular complexes as key factors in determining radiosensitivity in human malignant diseases. The present review delves into the biomedical contributions of specific mSWI/SNF subunits, including ARID1A, SMARCB1, SMARCA4, PBRM1, and BRD9, highlighting their pivotal roles in influencing tumor responses to radiotherapy. Evidence suggests that the loss of function in these subunits, often due to mutations, disrupts DNA repair pathways, thereby compromising genomic integrity and enhancing susceptibility to radiation-induced damage. Emerging preclinical studies have underscored the potential of exploiting these vulnerabilities through pharmacological targeting of mSWI/SNF complexes. Inhibition of these complexes can impair DNA damage repair mechanisms, creating a synthetic lethality effect by using a combined epigenetic therapy with ionizing radiation protocols. This dual approach not only amplifies the therapeutic efficacy of radiotherapy but also broadens the spectrum of potential strategies for oncological therapy. However, further investigation into the molecular mechanisms underlying these epigenetic interactions is essential for optimizing oncological therapies and paving the way for clinical applications aimed at enhancing radiotherapy outcomes in cancer patients.

Nonsense mutations or inactivation of SMARCA4 (BRG1) are associated with the histological manifestations of many undifferentiated tumors in humans. However, the relationship between SMARCA4 mutations and undifferentiated gallbladder cancer needs to be further elucidated. SMARCA4-deficient undifferentiated gallbladder cancer is a rare and highly malignant tumor. We present a patient with SMARCA4-deficient undifferentiated gallbladder cancer with genetic testing of related genes that revealed mutations at 2 loci. There are currently very few reports related to this tumor worldwide, and protocols for diagnosis and treatment are limited. Therefore, we collected and analyzed clinical data from this patient, along with relevant literature, to create a comprehensive summary.

SMARCA4 and SMARCA2, mutually exclusive catalytic ATPase subunits of human mammalian Switch/Sucrose-Nonfermentable chromatin remodeling enzymes, function as tumor suppressor genes. SMARCA4-deficient adenocarcinoma (SMARCA4-dADC) is a relatively rare subtype of TTF1/P40-negative non-small cell lung cancer. The concurrent presentation of SMARCA4-dADC and poorly differentiated adenocarcinoma with SMARCA2 (also known as BRM) loss in separate lobes of the same patient is even less common. This report describes such a case involving the simultaneous occurrence of these two tumor types in distinct locations within the lungs.

A 68-year-old male presented with a three-week history of vague pain in the right side of the chest, with no obvious trigger. Imaging revealed solid masses in the upper and lower lobes of the right lung with bilateral enlarged cervical lymph nodes. So, both of these masses underwent wedge resection. Histopathological examination confirmed that the lower lobe tumor was SMARCA4-dADC, while the upper lobe tumor was diagnosed as poorly differentiated adenocarcinoma. Although histologically similar, both exhibiting predominantly solid sheets and complex glandular structures, the two tumors displayed distinct immunohistochemical and molecular profiles. The lower lobe mass showed complete loss of BRG1 protein expression and partial loss of BRM. Immunohistochemical analysis revealed negative expression of TTF1, Napsin A, SALL4, CD34, and SOX2, and positive expression of CK7, pan-Cytokeratin (CK-pan), and HepPar-1. Molecular analysis identified mutations in SMARCA4, KRAS, and STK11. Conversely, the upper lobe mass retained BRG1 expression but showed complete loss of BRM protein expression, and negative expression of SALL4, CD34, and HepPar-1, positive expression of CK7, CK-pan, TTF1, Napsin A, and SOX2. A KRAS mutation was also detected in this tumor.

The simultaneous occurrence of SMARCA4-dADC and conventional adenocarcinoma in different locations within the same patient is exceedingly rare. However, the distinct immunophenotypic and molecular characteristics of SMARCA4-dADC differentiate it as a unique entity from conventional adenocarcinoma. We recommend including SMARCA4 in the marker panel used to evaluate TTF1-negative adenocarcinomas of potential or uncertain pulmonary origin. This report underscores the diagnostic challenge of concurrent SMARCA4-dADC and poorly differentiated adenocarcinoma, proposing a standardized immunohistochemical workflow to guide therapeutic decisions.

The SWI/SNF (switch/sucrose non-fermentable) related BAF (BRG1/BRM-related factor) chromatin remodeling complex subunit ATPase 4 (SMARCA4) is a gene with a high mutation frequency in the SWI/SNF complex. It plays a role as an ATP-dependent catalytic subunit, participates in remodeling chromatin structure and regulation of gene expression, and is closely related to the poor prognosis of malignant tumors. It is imperative to conduct a comprehensive investigation into the distinctive biological functions and mechanisms by which SMARCA4 contributes to cancer development and to devise targeted therapeutic strategies. Despite numerous studies associating SMARCA4 with the regulation of essential genes, ferroptosis, autophagy, lipid metabolism, and oxidative stress, the precise mechanisms of SMARCA4 in tumors remain unclear. Patients with SMARCA4 mutations exhibit a poor prognosis and demonstrate limited responsiveness to surgery, targeted therapies, immunotherapy, and chemotherapies. Thus, SMARCA4 emerges as a promising biomarker and therapeutic target. However, the development of more effective precision therapy tools remains an urgent unmet need. The unique molecular characteristics of SMARCA4 pose significant challenges for targeted drug development. Notably, the discovery of inhibitors targeting SMARCA4 synthetic lethal partners and associated pathways has marked a breakthrough in this field. Monotherapies directed against SMARCA4 face several limitations, including drug resistance, suboptimal objective response rates, and dose-limiting toxicities. Consequently, the exploration of combinatorial therapeutic strategies for SMARCA4 deficiency populations represents a critical direction for future clinical translation.

SMARCB1-deficient and SMARCA4-deficient sinonasal carcinomas are rare, with only a few systematic studies available in the literature. Secondary EWSR1 gene abnormalities have been reported in SMARCB1-deficient tumors. This study aimed to systematically investigate SWI/SNF complex-deficient sinonasal carcinomas in a single-institution cohort, perform clinicopathologic characterization, and explore the underlying molecular mechanisms.

Immunohistochemistry (IHC) of INI1 and BRG1 was performed on tissue microarrays containing tumor tissue from 149 consecutive sinonasal carcinomas. Single nucleotide polymorphism (SNP) array and EWSR1 gene fluorescence in situ hybridization (FISH) analyses were conducted on SMARCB1-deficient sinonasal carcinomas. Clinicopathologic characterization was studied.

Of the 149 sinonasal carcinomas, 7 (4.7%) showed SMARCB1 loss, while none demonstrated SMARCA4 loss. All patients were male and presented with advanced-stage tumors. Four SMARCB1-deficient sinonasal carcinomas exhibited basaloid morphology, two displayed eosinophilic tumor morphology, and one had mixed morphology. Homozygous and heterozygous SMARCB1 deletions were identified in 4/6 and 2/6 cases respectively. Heterozygous loss involving genes neighboring SMARCB1 gene, including EWSR1, was observed in four cases. One tumor showed a heterozygous loss of the entire chromosome 22q. EWSR1 FISH assay revealed concordant heterozygous EWSR1 loss in these five cases.

SMARCB1-deficient carcinomas account for 4.7% of sinonasal carcinomas in this single-institution cohort, while SMARCA4-deficient tumors are even rarer, with none identified. SMARCB1-deficient sinonasal carcinomas exhibit a broad spectrum of morphologic and immunohistochemical features. These carcinomas show complex genetic alterations, with homozygous SMARCB1 deletions present in the majority of cases.

Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin's lymphoma. The applicability of circulating tumor DNA (ctDNA) for predicting treatment response and prognosis in MCL remains underexplored.

This study included 34 MCL patients receiving first-line chemoimmunotherapy. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a noninvasive biomarker for treatment response and prognosis in MCL.

Commonly mutated genes in MCL included CCND1 (93.5%), ATM (48.4%), KMT2D (25.8%), and TP53 (25.8%). Subgroup analysis of tissue samples showed that CDKN2A mutations (P = 0.028), along with alterations in BCR and TCR signaling (P = 0.004) and the PI3K pathway (P = 0.008), were enriched in the blastoid subtype. ATM mutations (P = 0.041) were more prevalent in MIPI-low patients, while epigenetic chromatin remodeling pathway alterations (P = 0.028) were more common in MIPI-high patients. Plasma ctDNA demonstrated high sensitivity for detecting structural variants (96.6%), followed by mutations (71.3%) and copy number variants (30.0%). 75% of patients exhibited moderate-to-high concordance in detecting genomic variants between plasma and tissue samples. Pretreatment ctDNA levels exhibited high specificity in predicting clinical efficacy but had a suboptimal sensitivity of 68.2%. Higher ctDNA levels were significantly associated with shorter progression-free survival (PFS; P = 0.002) and overall survival (OS; P = 0.009). Additional ctDNA-based genetic features associated with shorter PFS included TP53 (P = 0.002), TRAF2 (P = 0.023), and SMARCA4 (P = 0.023) mutations, while TP53 (P = 0.006) and TERT (P = 0.031) mutations predicted shorter OS. Persistent positive ctDNA in post-treatment plasma samples indicated molecular relapse and poor prognosis, whereas undetectable ctDNA defined a subset of patients with favorable survival outcomes.

This study identified plasma ctDNA as a promising biomarker that noninvasively captures tumor-derived genetic variants associated with treatment response and survival outcomes in MCL, highlighting the clinical value of ctDNA for diagnosis, recurrence prediction, and surveillance monitoring.

Predictive biomarker identification in cancer treatment has traditionally relied on pre-defined analyses, limiting discoveries to expected biomarkers and potentially overlooking novel ones predictive of therapy response. In this work, we develop a novel machine-learning approach capable of exploring full landscape of mutations and combinations and identify potentially new predictive biomarkers for chemoimmunotherapy. Utilizing the liquid biopsy dataset from 313 non-small cell lung cancer (NSCLC) patients in the Phase 3 Impower150 trial (NCT02366143), we developed the HRdiffRF algorithm with a novel hazard ratio-splitting criterion. Predictive mutations and combinations were identified for overall survival (OS) improvement with atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) compared to bevacizumab plus carboplatin and paclitaxel (BCP). Our analysis confirms the predictive role of KRAS mutations and reveals the predictive value of PTPRD and SMARCA4 mutations in chemoimmunotherapy efficacy. Unlike other KRAS wild-type NSCLC patients, NSCLC patients with KRAS wild-type status and mutations in FAT1, ERBB2, or PTPRD may benefit from chemoimmunotherapy, while NTRK3 and GNAS mutations could negatively impact survival. Patients harboring concurrent KRAS and KEAP1 mutations may not benefit from chemoimmunotherapy. These findings highlight the complex genetic factors influencing treatment response for chemoimmunotherapy in NSCLC. In summary, the proposed machine-learning tool identified potential predictive biomarkers for first-line chemoimmunotherapy in NSCLC and can be readily applied to other tumor types and studies. It can also be extended to explore predictive biomarkers beyond mutations.

In 2021, the fifth edition of the World Health Organization (WHO) classification of thoracic tumors introduced a new category, "Thoracic SMARCA4-deficient undifferentiated tumor", highlighting SMARCA4 deficiency as a key molecular marker for classifying as "other pulmonary epithelial tumors". SMARCA4 is a gene encoding a protein involved in chromatin remodeling, and approximately 8% of non-small cell lung cancer (NSCLC) patients exhibit SMARCA4 deletions. These patients are more prone to drug resistance, early recurrence, and unfavorable clinical outcomes. Moreover, NSCLC patients with concomitant SMARCA4 mutations may not benefit from currently available treatments, underscoring the distinctiveness of this subgroup. Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) represent distinct entities from SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC). This distinction is supported by their divergent pathological characteristics, demographic profiles, and survival outcomes. NSCLC cases deficient in SMARCA4 exhibit high malignancy, yet the precise biological mechanisms underlying this phenomenon remain under intensive investigation. Pathological examination and immunohistochemistry can effectively differentiate SMARCA4-UT from SMARCA4-dNSCLC. SMARCA4-UT typically manifests as adenocarcinoma or, more rarely, as squamous cell carcinoma with undifferentiated rhabdomyoblastic morphology. Therefore, elucidating the mechanisms underlying SMARCA4 alterations in NSCLC and their regulatory roles in tumorigenesis and the microenvironment is crucial. This article aims to discuss the structure, biological functions, significance in NSCLC development, and emerging potential therapeutic strategies related to SMARCA4 while providing clinical practice guidance for NSCLC patients with SMARCA4 deletions.

SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-UT) are very aggressive high-grade malignant tumors associated with poor prognosis. It is typically diagnosed at an advanced stage. Response to conventional therapeutic approaches is particularly poor and there is no specific targeted drug for this mutation site. Currently, there are no guidelines regarding the standard treatment for this disease.

In November 2021, a 71-year-old Chinese male was diagnosed with metastatic SMARCA4-UT in liver and brain. Molecular analysis showed a TP53 mutation in exon 10 and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of <1%. From January 2022, the patient received a combination of camrelizumab, bevacizumab, pemetrexed, and carboplatin for four cycles, followed by camrelizumab, bevacizumab, and pemetrexed maintenance therapy for 31 cycles. The last treatment was on June 25, 2024. Imaging follow-up revealed a tumor reduction of approximately 50% as the best response. To date, the progression-free survival (PFS) has surpassed 32 months.

To our knowledge, this is the first patient with SMARCA4-UT treated with this regimen. The first-line combined regimen containing immunotherapy plus antiangiogenic therapy and chemotherapy demonstrated durable treatment response in this case. This may represent a novel treatment option for this group of patients. Prospective studies will be required to validate the efficacy and safety of this therapy.

Gastric SMARCA4-deficient undifferentiated tumors are rare and have a poor prognosis. We analyzed two cases of gastric SMARCA4-deficient undifferentiated tumors with clinicopathologic characteristics, treatment and flow-up.

Immunohistochemistry was used to evaluate the expression of BRG1 (SAMRCA4), SMARCB1 (INI-1), CKpan, Ki-67, CD3, CD20, CD163, PD-1, and PD-L1 in gastric SMARCA4-deficient undifferentiated tumors. Additionally, the clinical characteristics, imaging features, diagnosis, and treatment were analyzed.

Two elderly male patients (69 and 61 years old) with a large ulcerated mass located in the gastric fundus and cardia. Histologically, the tumor is of low adhesion, diffusely infiltrating lamellar growth, without any percentage of epithelial differentiation zones, and with little stromal component. Tumor cells round, oval, a small amount of irregular shape, easy to see mitotic figures. Some of them had obvious nucleoli, and a few had multiple nucleoli. The cytoplasm varies, and some cells are more abundant. Significant vascular and neural invasion. BRG1(SMARCA4) was absent, INI-1 was present, and Ki-67 proliferation index was highly expressed (≥ 80%). The remaining sarcoma-specific markers were negative. In case 1, the epithelial markers were negative and the PD-L1 combined positive score was 5. In case 2, CKpan was weakly expressed in only a dozen cells, and the PDL1 CPS was 10. The two patients received chemotherapy and anti-PD1 immunotherapy after radical gastrectomy for gastric cancer. The postoperative follow-up time of the two patients was 16 (case 1) and 3 months (case 2), respectively. The general condition was good, no recurrence or metastasis was observed, and the plasma tumor markers were in the normal range.

Large SMARCA4-deficient tumors are more likely to have massive necrosis on the surface, leading to negative biopsy results. This tumor has a diffuse lamellar growth and needs to be differentiated from a variety of tumors with similar morphology, such as lymphoma, malignant melanoma, neuroendocrine carcinoma and undifferentiated sarcoma. The tumor cells were negative or only slightly positive for CKpan increases the difficulty of pathological diagnosis of this disease. However, loss of BRG1 (SMARCA4) expression can confirm the diagnosis. Chemotherapy combined with anti-PD1 treatment may have potential benefits in the management of gastric SMARCA4-deficient undifferentiated tumors. However, given the rarity of these tumors and the limited number of cases in our study, further research with larger cohorts is needed to validate these preliminary results.

SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC) typically lacks target-driven gene alterations and are primarily resistant to cytotoxic drugs. There is currently no standard treatment, especially for those who are unwilling or unable to receive chemotherapy. This case reported that chemotherapy-free strategy with tislelizumab and fruquintinib was utilized as a first-line treatment for a patient with SMARCA4-deficient NSCLC, and the patient achieved remarkable partial remission and lasted more than two years of disease control without severe adverse events.

Acute Myeloid Leukemia (AML) is a devastating hematologic malignancy. Chemotherapy remains the primary treatment, offering rapid disease control and potential complete remission. However, more than half of the patients develop resistance and relapse, significantly reducing patient survival. Research has shown that drug-resistance and recurrence of AML are closely linked to leukemic stemness. Consequently, discovering new anti-Leukemia stem cell (LSC) compounds is a promising strategy for the treatment of AML in clinic. Additionally, the recent focus on inducing non-apoptotic programmed cell death in AML cells presents an alternative direction for therapeutic drug development, targeting current anti-apoptotic pathways. In this study, novel Sitolactone analogues, potential anti-LSCs compounds, were designed and synthesized based on the "biomimetic design" strategy. Compound 42 was found to significantly inhibit proliferation of AML cells. Subsequent biological evaluation revealed that this compound not only reduced the population of LSCs but also effectively induced PANoptosis in AML cells. Given the active compound's poor water solubility, a prodrug modification strategy was employed to enhance in vivo delivery with superior oral bioavailability and PK properties. This approach significantly suppressed AML cell growth in a mouse orthotropic model with favorable in vivo tolerance.

Cancer progression and therapeutic resistance are closely linked to a stemness phenotype. Here, we introduce a protein-expression-based stemness index (PROTsi) to evaluate oncogenic dedifferentiation in relation to histopathology, molecular features, and clinical outcomes. Utilizing datasets from the Clinical Proteomic Tumor Analysis Consortium across 11 tumor types, we validate PROTsi's effectiveness in accurately quantifying stem-like features. Through integration of PROTsi with multi-omics, including protein post-translational modifications, we identify molecular features associated with stemness and proteins that act as active nodes within transcriptional networks, driving tumor aggressiveness. Proteins highly correlated with stemness were identified as potential drug targets, both shared and tumor specific. These stemness-associated proteins demonstrate predictive value for clinical outcomes, as confirmed by immunohistochemistry in multiple samples. The findings emphasize PROTsi's efficacy as a valuable tool for selecting predictive protein targets, a crucial step in customizing anti-cancer therapy and advancing the clinical development of cures for cancer patients.

BRG1 deficiency in patients with lung adenocarcinoma that has metastasized to the brain, termed BRG1-deficient brain metastasis lung adenocarcinoma, is an uncommon event. Prior to this study, these patients had not undergone extensive molecular and (epi)genetic analysis. We report a comprehensive clinical, histopathologic, and molecular assessment of 9 BRG1-deficient brain metastasis lung adenocarcinoma cohort (BRG1-deficient BM cohort) in comparison with a 16 BRG1-retained brain metastasis lung adenocarcinoma cohort (BRG1-retained BM cohort). Patients with BRG1-deficient BM exhibited a significantly increased risk of mortality. Molecular analysis revealed a high prevalence of mutations in SMARCA4 and TP53 genes within this group. DNA methylation molecular diagnostics showed a high rate of genomic instability and a markedly lower DNA methylation age in these patients. Functional enrichment analysis of differentially methylated genes suggested that hypomethylation genes were primarily associated with the negative regulation of neuron differentiation, G protein-coupled receptor signaling pathways, and cell differentiation. Conversely, hypermethylation was linked to the regulation of small GTPase mediated signal transduction, Rho protein signal transduction, DNA damage response, and apoptotic processes. This study investigated a rare subgroup of lung adenocarcinoma patients with brain metastasis characterized by BRG1 deficiency and a poor prognosis. Our study not only provides a comprehensive multi-omic data resource but also provides valuable biological insights into patients. The findings may serve as a valuable reference for the future pathological diagnosis of BRG1-deficient brain metastasis in lung adenocarcinoma patients.

BackgroundSMARCA4-deficient NSCLC is a rare type of tumor, accounting for approximately 10% of all NSCLC. It exhibits a weak response to conventional chemotherapy and has a poor prognosis, and lacks alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1) genes Therefore, the mechanisms of SMARCA4 in NSCLC development urgently need to be explored to identify novel biomarkers and precise therapeutic strategies for this subtype.ObjectiveThe aim of this study was to understand the clinical characteristics of this special type of tumor and its response to different treatments.MethodsWe collected clinical data from 42 patients with SMARCA4-deficient NSCLC from July 2022 to January 2024, and analyzed their clinical features and survival state.ResultsThe study included a total of 42 patients diagnosed with NSCLC and harboring SMARCA4 mutation. The majority of these patients were male with a median age of 67 years. Most patients presented at stage IV upon diagnosis with highly aggressive tumors characterized by high Ki-67 proliferation index values resulting in poor overall prognosis. Genetic testing revealed TP53 gene mutations to be most prevalent (21%), followed by KRAS mutations (13%). Patients receiving immunotherapy exhibited significantly longer median overall survival compared to those treated solely with chemotherapy. Targeted drug therapy demonstrated favorable effects in some patients.ConclusionNSCLC patients harboring SMARCA4 deficiency exhibit poor overall survival rates with a median overall survival time of 5.4 months. Immunotherapy may provide benefits for NSCLC patients with SMARCA4 deficiency.

SMARCA4 is a catalytic subunit of the SWItch/sucrose non-fermentable (SWI/SNF) complex. Truncating SMARCA4 germline pathogenic variants (PVs) lead to rhabdoid tumor predisposition syndrome type 2 (RTPS2), associated with small cell carcinoma of ovary hypercalcemic type (SCCOHT) and pediatric rhabdoid tumors. To our knowledge, no primary bone neoplasm with SMARCA4 loss is reported in the literature. We describe a primary high-grade sarcoma in the femur of a 13-year-old patient with undocumented germline history and without other lesions. The tumor showed morphologic features reminiscent of a "teratocarcinosarcoma," including high-grade primitive spindle and round cell morphology, low-grade fibroblastic proliferation, high-grade glandular epithelium, and low-grade squamous and mucinous epithelium. The tumor showed diffuse loss of SMARCA4 immunoexpression. We subsequently identified a heterozygous nonsense SMARCA4 PV in the patient's germline, with copy-neutral loss of heterozygosity in the tumor. Our report expands the spectrum of SMARCA4-deficient tumors, with implications for germline tumor predisposition and surveillance.

SMARCA4/BRG1-deficient non-small cell lung cancer (S/B-d NSCLC) is a rare subtype of non-small cell lung cancer (NSCLC). The aim of this study was to investigate the clinical, imaging, serum tumor marker, and pathological features of S/B-d NSCLC, particularly computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) scan features.

Our analysis included 23 patients with pathologically confirmed S/B-d NSCLC from January 2021 to December 2023. A retrospective analysis of clinical, serum tumor markers, imaging [including CT, FDG PET/CT, magnetic resonance imaging (MRI)], pathological features, treatment protocols, and follow-up results was performed. Independent samples t-tests were used to assess statistical differences in short diameters and maximum standardized uptake value (SUVmax) between groups.

S/B-d NSCLC occurs predominantly in male patients with a history of smoking and a mean age of 62.78 years (39-77 years). S/B-d NSCLC was found incidentally during physical examination in 56.52% of patients. The CT scan features were as follows: predominantly tumors (72.73%), peripheral in the lungs (77.27%), round or roundish morphology (81.28%), pleural or vascular invasion (95.46%), and moderately to severely enhanced (59.09%). The FDG PET/CT showed FDG-avid with mean SUVmax of 14.78±9.57. Lung cancer-related serum tumor markers had high positivity rates for carcinoembryonic antigen (CEA) (66.67%), recombinant cytokeratin fragment antigen 21-1 (CYFRA21-1) (61.91%), and carbohydrate antigen 125 (CA125) (57.14%). Pathological features are often characterized by grading (poor differentiation, 100%), tumor spread through the air space (STAS, 85.71%), and vascular invasion (85.71%). Immunohistochemistry showed that SMARCA4 (BRG1) was absent, and P40, P63, ALK-Ventana ALK (D5F3), and p-TRK were often negative. Genetic tests showed that the positivity rate of TP53 (76.92%) and KEAP1 (53.85%) was high. Despite diverse treatment options being available, high rates of progression during treatment and poor prognosis were observed. Among CT features (N=22), the short diameter of CT-diagnosed metastatic lymph nodes (LNs) was larger than that of non-metastatic LNs, and the difference was statistically significant (P=0.02). Among the FDG PET/CT features (N=12), SUVmax was larger in tumor group than lesion group, SUVmax was larger in M1 group than M0 group, and the difference was statistically significant in both groups (P=0.001 and P=0.04).

S/B-d NSCLC has distinct features in epidemiology, serum tumor markers, imaging, and pathology. In particular, FDG-avid is evident in the FDG PET/CT scan. The size of the lesion and the degree of FDG avidity provide information about the degree of malignancy and the high probability of distant metastasis in S/B-d NSCLC. FDG PET/CT is recommended when S/B-d NSCLC is suspected based on CT features, especially for large lesions. The FDG PET/CT scan can help with accurate staging and individual treatment planning.

BRM (SMARCA2) and BRG1 (SMARCA4) are mutually exclusive ATPase subunits of the mSWI/SNF (BAF) chromatin remodeling complex. BAF is an attractive therapeutic target because of its role in transcription, and mutations in the subunits of BAF are common in cancer and neurological disorders. Herein, we report the discovery of compound 1 (FHD-286) as a potent allosteric inhibitor of the dual ATPase subunits from a high-throughput screening hit with a BRM IC50 of ∼27 μM. FHD-286 is an orally bioavailable compound with antitumor activity in mouse xenograft models of uveal melanoma and acute myeloid leukemia and is being evaluated in Phase 1 clinical trials.

Our objective was to examine the clinical and genetic features of Coffin-Siris syndrome resulting from a pathogenic variant in the SMARCA4 gene.

The clinical data and molecular genetic test results of a newbron with Coffin-Siris syndrome involving a pathogenic variant in the SMARCA4 gene were retrospectively analyzed, and the related literatures were reviewed.

A newborn exhibited inspiratory dyspnea following birth and developmental anomalies (coarse appearance, thick hair, long eyelashes, broad nasal tip, flat nasal bridge, thin upper lip, thick lower lip, digital anomalies, cleft palate, supraglottic laryngeal chondromalacia, stenosis of the left upper bronchus and hypotonia). Whole exome sequencing revealed a heterozygous missense variant in SMARCA4 gene (NM_003072.5 c.3127C > T, p.Arg1043Trp). Parents did not find the above pathogenic variant, which was a new pathogenic variant. In addition to our case, we also retrieved 22 cases of Coffin-Siris Syndrome in SMARCA4 gene variation, which is a congenital multi-system dysfunction syndrome characterized by abnormal appearance and developmental retardation. The common otolaryngologic features of 23 patients with CSS in SMARCA4 gene variant included palate abnormalities, feeding difficulties, ear abnormalities and hearing loss.

Coffin-Siris syndrome is a rare genetic disease inherited in an autosomal-dominated manner. It is often associated with malformations in the otorhinolaryngologic system. This case has many common features with previously reported CSS cases with pathogenic variant in the SMARCA4 gene, which further characterizes the performance of the pathogenic variant, suggesting that palatal abnormalities may be a significant feature of the genotype. For patients with developmental abnormalities, whole-genome sequencing or whole-exome sequencing is particularly important to assist diagnosis. Currently, there is no known treatment for CSS, and individuals with CSS experience various complications affecting multiple systems.

A 50-year-old man presented with a bulky mass in the left thigh and was referred to our department. He showed an impaired Eastern Cooperative Oncology Group performance status of 3 due to swelling of the left thigh and pain. Imaging analysis revealed a large mass measuring 16 cm in the left thigh and right forearm, along with the bilateral adrenal gland, right lung, right axillary lymph nodes, liver, and left femur. Despite additional tests, including pathological examination, the primary origin of the tumors could not be identified. Because of the rapid tumor progression, he was placed on nivolumab (NIVO; 240 mg/body, every 2 weeks) monotherapy based on the diagnosis of cancer of unknown primary, unfavorable type. Simultaneous comprehensive genomic profiling (CGP) test revealed a high tumor mutation burden (15.69 Muts/Mb) and a truncating mutation of SMARCA4, along with loss of BRG1 expression detected by additional immunohistochemical (IHC) analysis. Based on the predominance of soft tissue in the lesion, histological and IHC findings, and genomic phenotype, the patient was finally re-diagnosed with SMARCA4-deficient, SMARCB1/INI-1-preserved epithelioid sarcoma (ES). He showed a dramatic improvement in physical and laboratory findings at 5 weeks after the initial NIVO dose. Although he experienced immune-related adverse events, such as liver dysfunction, colitis and relative adrenal failure, and severe sepsis due to pulmonary cyst infection, he was able to overcome these complications. By the 12th dose of NIVO (13 months after the initial treatment), he has exhibited a positive response to NIVO without any additional complications. Among SMARCA4-deficient tumors, there have been multiple reports on the sensitivity of SMARCA4-deficient thoracic tumors to immune checkpoint inhibitors (ICIs), including PD-1 blockade agents. This case indicates that SMARCA4-deficient SMARCB1/INI-1-preserved ES may share molecular pathological characteristics with SMARCA4-deficient thoracic tumors, given their similar sensitivity to ICIs. In addition, CGP may play an important role in hypothesizing the primary site of tumors and guiding treatment selection for rare cancers, as in the present case, which lacks established treatment options. Further data accumulation is essential to validate this approach.

SMARCA4-deficient lung cancer, including thoracic SMARCA4-deficient undifferentiated tumors and SMARCA4-deficient nonsmall-cell lung carcinomas, is a rare and aggressive disease characterized by rapid progression and poor prognosis. This cancer was identified as a distinct entity with specific morphologic and molecular features in the 2021 WHO Classification of Thoracic Tumors. Molecular alterations in SMARCA4 are specific to this type of lung cancer. Deficiency in SMARCA4 suppresses the SWI/SNF tumor suppressor complex, driving tumor progression. Due to the lack of standardized treatment, most patients succumb to the disease within 6 months. This study provides a detailed analysis of the SMARCA4 pathway and its role in lung cancer. We analyzed potential therapeutic targets and agents to offer insights for the precise and effective treatment of SMARCA4-deficient lung cancer.

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. Brahma-related gene 1 (BRG1), as a catalytic ATPase, is a major regulator of gene expression and is known to mutate and overexpress in HCC. The purpose of this study was to investigate the mechanism of action of BRG1 in HCC cells. In our study, BRG1 was silenced or overexpressed in human HCC cell lines. Transwell and wound healing assays were used to analyze cell invasiveness and migration. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) detection were used to evaluate mitochondrial function in HCC cells. Colony formation and cell apoptosis assays were used to evaluate the effect of BRG1/TOMM40/ATP5A1 on HCC cell proliferation and apoptosis/death. Immunocytochemistry (ICC), immunofluorescence (IF) staining and western blot analysis were used to determine the effect of BRG1 on TOMM40, ATP5A1 pathway in HCC cells. As a result, knockdown of BRG1 significantly inhibited cell proliferation and invasion, promoted apoptosis in HCC cells, whereas BRG1 overexpression reversed the above effects. Overexpression of BRG1 can up-regulate MMP level, inhibit mPTP opening and activate TOMM40, ATP5A1 expression. Our results suggest that BRG1, as an oncogene, promotes HCC progression by regulating TOMM40 affecting mitochondrial function and ATP5A1 synthesis. Targeting BRG1 may represent a new and effective way to prevent HCC development.

SWI/SNF (Switch/Sucrose non-fermentable, switch/sucrose non-fermentable) chromatin remodeling complex is a macromolecular complex composed of multiple subunits. It can use the energy generated by the hydrolysis of ATP (Adenosine triphosphate) to destroy the connection between DNA and histones, achieve the breakdown of nucleosomes, and regulate gene expression. SWI/SNF complex is essential for cell proliferation and differentiation, and the abnormal function of its subunits is closely related to tumorigenesis. Among them, ARID1A, an essential non-catalytic subunit of the SWI/SNF complex, can regulate the targeting of the complex through DNA or protein interactions. Moreover, the abnormal function of ARID1A significantly reduces the targeting of SWI/SNF complex to genes and participates in critical intracellular activities such as gene transcription and DNA synthesis. As a catalytic subunit of the SWI/SNF complex, SMARCA4 has ATPase activity that catalyzes the hydrolysis of ATP to produce energy and power the chromatin remodeling complex, which is critical to the function of the SWI/SNF complex. The study data indicate that approximately 25% of cancers have one or more SWI/SNF subunit genetic abnormalities, and at least nine different SWI/SNF subunits have been identified as having repeated mutations multiple times in various cancers, suggesting that mutations affecting SWI/SNF subunits may introduce vulnerabilities to these cancers. Here, we review the mechanism of action of ARID1A and SMARCA4, the two subunits with the highest mutation frequency in the SWI/SNF complex, and the research progress of their targeted therapy in tumors to provide a new direction for precise targeted therapy of clinical tumors.

Pediatric lymphoepithelioma-like carcinoma (pLELC) is a rare neoplasm with unclear prognosis, genome, and tumor microenvironment. Our study aims to elucidate its genomic and clinical characteristics.

Forty-one pLELC patients were enrolled at Sun Yat-sen University Cancer Center from 2012 to 2023. Kaplan-Meier analysis was utilized to estimate progression-free survival (PFS) and overall survival (OS). Baseline plasma protein levels from 16 patients and 9 health controls were analyzed using a Olink proteomic platform and whole exon sequence (WES) was performed on 11 tumor samples from 10 pediatric patients. Immunohistochemistry (IHC) for PD-L1was performed, and the infiltration of CD4+ or CD8+ T cells was evaluated.

Patients receiving anti PD-1 in combination with chemotherapy had a 1-year PFS of 100%, while the 2-year PFS was 72.92% (95%CI: 46.80‒100%). The 1-year OS for patients receiving anti PD-1 in combination with chemotherapy was 100%, and the 2-year OS was 87.5% (95%CI: 67.34-100%). Significant upregulation of immune checkpoint molecules was detected including LAG-3, PD-L1, and galectin-9 in LELC group by proteomic analysis (P < 0.05). The mutational landscape of pediatric LELC presented more genes mutated in pathways associated with immune, DNA repair, cell cycle and NOTCH. Pathway analysis of mutational profiles indicated DNA repair pathway and SWI/SNF complex were potential drug targets for pLELC patients. All the pediatric LELC patients evaluated exhibited positive PD-L1 expression and CD4+/CD8+ T cells infiltration.

Our findings indicate a promising response rate associated with the combination of PD-1 antibody treatment and chemotherapy in pediatric patients with LELC, providing a theoretical basis for targeting DNA repair pathways. These outcomes suggest that clinical trials involving immune checkpoint inhibitors are warranted in pediatric patients with LELC.

TFE3-rearranged Renal Cell Carcinoma (TFE3-RCC) is an aggressive subtype of RCC characterized by Xp11.2 rearrangement, leading to TFE3 fusion proteins with oncogenic potential. Despite advances in understanding its molecular biology, effective therapies for advanced cases remain elusive. This study investigates the role of ARID2, a component of the SWI/SNF chromatin remodeling complex, in TFE3-RCC. Through a series of in vitro and in vivo experiments, we confirmed that ARID2 acts as a tumor suppressor in TFE3-RCC. ARID2 knockout (KO) enhanced TFE3-RCC cell migration, proliferation, and tumor growth. Transcriptomic analysis revealed ERBB3 as a key target gene regulated by both PRCC-TFE3 and ARID2. Chromatin immunoprecipitation (ChIP) assays demonstrated that PRCC-TFE3 directly binds to and upregulates ERBB3 expression, with ARID2 KO further enhancing this effect. TFE3-RCC ARID2 KO cells exhibited significant gene expression enrichment in MAPK and ERBB3 signaling pathways. These cells also showed increased activation of ERBB3, EGFR, and selective activation of SRC and MAPK. TFE3-RCC ARID2 KO cells demonstrated heightened sensitivity to the ERBB3 inhibitor AZD8931 compared to their wild-type counterparts, exhibiting significantly reduced migration and proliferation rates. These findings suggest that the PRCC-TFE3-ARID2-ERBB3 axis plays a critical role in TFE3-RCC pathogenesis and highlights the potential of targeting ERBB3 in ARID2-deficient TFE3-RCC as a therapeutic strategy. This study provides new insights into the molecular mechanisms of TFE3-RCC and suggests avenues for precision treatment of this aggressive cancer.

The switch/sucrose non-fermenting (SWI/SNF) complex family includes important chromatin-remodeling factors that are frequently mutated in lung adenocarcinoma (LUAD). However, the role of one family member, SMARCA4, in LUAD prognosis and immunotherapy sensitivity remains unclear. In the present study, 6745 LUAD samples from the cBioPortal database were used to analyze the relationships between SMARCA4 mutations and patient prognoses and clinical characteristics. Additionally, we examined the correlation between SMARCA4 mutations and prognosis in patients treated with immunotherapy using two immune-related datasets. SMARCA4 mutations and low expression were associated with shorter survival, and mutations were associated with a high tumor mutational burden and high microsatellite instability. SMARCA4 mutations were accompanied by KRAS, KEAP1, TP53 and STK11 mutations. No significant difference was observed in the immunotherapy response between patients with and without SMARCA4 mutations. When KRAS or STK11 mutations were present, immunotherapy effectiveness was poorer; however, when both SMARCA4 and TP53 mutations were present, immunotherapy was more effective. Furthermore, low SMARCA4 expression predicted a higher immunophenoscore, and SMARCA4 expression was correlated with certain immune microenvironment features. Taken together, our results suggest that SMARCA4 mutations and low expression might be associated with poor LUAD prognosis. Additionally, immunotherapy efficacy in patients with SMARCA4 mutations depended on the co-mutant genes. Thus, SMARCA4 could be an important factor to be considered for LUAD diagnosis and treatment.

Craniopharyngiomas, including adamantinomatous (ACP) and squamous papillary (PCP) types, are challenging to treat because of their proximity to crucial pituitary structures. This study aimed to characterize the cellular composition, tumor tissue diversity, and cell-cell interactions in ACPs and PCPs using single-cell RNA sequencing. Single-cell clustering revealed diverse cell types, further classified into developing epithelial, calcification, and immune response for ACP and developing epithelial, cell cycle, and immune response for PCP, based on gene expression patterns. Subclustering revealed the enrichment of classical M1 and M2 macrophages in ACP and PCP, respectively, with high expression of pro-inflammatory markers in classical M1 macrophages. The classical M1 and M2 macrophage ratio significantly correlated with the occurrence of diabetes insipidus and panhypopituitarism. Cell-cell interactions, particularly involving CD44-SPP, were identified between tumor cells. Thus, we developed a comprehensive cell atlas that elucidated the molecular characteristics and immune cell inter-networking in ACP and PCP tumor microenvironments.

In recent years, significant strides in both conceptual understanding and technological capabilities have bolstered our comprehension of the factors underpinning cancer initiation and progression. While substantial insights have unraveled the molecular mechanisms driving carcinogenesis, there has been an overshadowing of the critical contribution made by epigenetic pathways, which works in concert with genetics. Mounting evidence demonstrates cancer as a complex interplay between genetics and epigenetics. Notably, epigenetic elements play a pivotal role in governing alternative pre-mRNA splicing, a primary contributor to protein diversity. In this review, we have provided detailed insights into the bidirectional communication between epigenetic modifiers and alternative splicing, providing examples of specific genes and isoforms affected. Notably, succinct discussion on targeting epigenetic regulators and the potential of the emerging field of epigenome editing to modulate splicing patterns is also presented. In summary, this review offers valuable insights into the intricate interplay between epigenetics and alternative splicing in cancer, paving the way for novel approaches to understanding and targeting this critical process.

Metabolic reprogramming plays a pivotal role in cancer progression, contributing to substantial intratumour heterogeneity and influencing tumour behaviour. However, a systematic characterization of metabolic heterogeneity across multiple cancer types at the single-cell level remains limited.

We integrated 296 tumour and normal samples spanning six common cancer types to construct a single-cell compendium of metabolic gene expression profiles and identify cell type-specific metabolic properties and reprogramming patterns. A computational approach based on non-negative matrix factorization (NMF) was utilised to identify metabolic meta-programs (MMPs) showing intratumour heterogeneity. In-vitro cell experiments were conducted to confirm the associations between MMPs and chemotherapy resistance, as well as the function of key metabolic regulators. Survival analyses were performed to assess clinical relevance of cellular metabolic properties.

Our analysis revealed shared glycolysis upregulation and divergent regulation of citric acid cycle across different cell types. In malignant cells, we identified a colorectal cancer-specific MMP associated with resistance to the cuproptosis inducer elesclomol, validated through in-vitro cell experiments. Furthermore, our findings enabled the stratification of patients into distinct prognostic subtypes based on metabolic properties of specific cell types, such as myeloid cells.

This study presents a nuanced understanding of multilayered metabolic heterogeneity, offering valuable insights into potential personalized therapies targeting tumour metabolism.

National Key Research and Development Program of China (2021YFA1300601). National Natural Science Foundation of China (key grants 82030081 and 81874235). The Shenzhen High-level Hospital Construction Fund and Shenzhen Basic Research Key Project (JCYJ20220818102811024). The Lam Chung Nin Foundation for Systems Biomedicine.

SMARCB1/SMARCA4-deficient malignancies of the female genital tract are rare entities, characterized by similar histologic features, such as sheet-like growth patterns and rhabdoid cells. Previous studies have shown mutually exclusive loss of SMARCA4/BRG1 and SMARCB1/INI1. Herein, we describe a unique cervical mixed carcinoma in a 77-year-old patient. The tumor consisted of 3 components, gastric-type adenocarcinoma, squamous carcinoma, and undifferentiated carcinoma. While the undifferentiated carcinoma was negtive for CK7, CK5/6 and p63, it was positive for pan-CK. DNA-based next-generation sequencing revealed a nonsense mutation in SMARCA4, copy number loss in SMARCB1, and a nonsense mutation in ARID1A. Different molecular alterations of the switch/sucrose nonfermenting complex subunits in the present case may provide further insights into the functions of the switch/sucrose nonfermenting complex in the progression of tumors.

SMARCA4 (BRG1) is a core unit of the SWI/SNF complex, regulating gene transcription through chromatin remodeling. Germline SMARCA4 variants have been reported to be associated with various malignancies. Here, we report the first case of extraskeletal Ewing sarcoma in a young female patient with a germline pathogenic variant of SMARCA4 (c.3546 + 1G>A), diagnosed with next generation sequencing (NGS). This alteration was also identified in her familial lineage, including her sister who was previously diagnosed with small cell carcinoma of the ovary, hypercalcemic type, a malignancy highly associated with SMARCA4 mutations. Despite undergoing radical surgery and receiving systemic treatments including VeIP (vinblastine, ifosfamide, cisplatin), and VDC (vincristine, doxorubicin, cyclophosphamide) regimens, the patient succumbed to death due to disease progression. With the implementation of NGS, we anticipate that more cases with SMARCA4 mutations will be diagnosed in the future. Further research is necessary to unveil therapeutic targets associated for this oncogenic alteration.

SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are a newly described entity and are typically seen in the thoracic cavity. However, these tumors have been described in other body sites, including the esophagus. These tumors are rare, aggressive neoplasms, characterized by the loss of protein product of SMARCA4 (Brahma-related gene-1) and the preservation of INI1 (SMARCB1) expression. Here, we present two tumors of SMARCA4-UT of the esophagus with its microscopic appearance and immunohistochemical profile. We also include a literature review of SMARCA4-deficient tumors of the tubular gastrointestinal tract with their immunohistochemical and mismatch repair profiles for each specimen. Due to its non-specific histologic appearance and variable staining in expanded immunohistochemical panels, this tumor frequently overlaps with other tumor types, making the diagnosis of SMARCA4-UT challenging. These tumors are often associated with intestinal metaplasia of the esophagus and are thought to represent a high-grade undifferentiated transformation of a conventional esophageal adenocarcinoma. These tumors are typically associated with poor clinical outcomes and have poor response to conventional therapies. Currently, there are no standard guidelines for treatment of these tumors; however, palliative radiotherapy and systemic chemotherapy may provide benefit. More recently, immunotherapy and novel therapeutic targets have shown some promise for these patients.

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42-67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69-100% of SCCOHT cases and SMARCA2 silencing seen 86-100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.

Undifferentiated gastric carcinoma, characterized by anaplastic cells lacking distinct features of cytological or architectural differentiation, poses diagnostic and therapeutic challenges. Recent studies have suggested an association between this carcinoma and deficiencies in the SWI/SNF complex, particularly mutations in subunits such as SMARCA4. We herein report six cases of SMARCA4-deficient undifferentiated gastric carcinoma with molecular findings, highlighting the rarity and diagnostic pitfalls of this malignancy. Predominantly occurring in males over 50 years, these cases presented with nonspecific symptoms and were often diagnosed at an advanced stage. Histologically, the tumors exhibited a sheet-like growth pattern, reduced or absent epithelial markers, and loss of BRG-1 expression, with molecular analysis confirming SMARCA4 gene mutations. The response to conventional chemotherapy was poor, underscoring the importance of complete surgical resection and the development of alternative treatment modalities.