Auswahl der wissenschaftlichen Literatur zum Thema „SMARCA4-UT“

Background Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a distinct clinicopathological entity with an aggressive clinical course. Additionally, SMARCA4/BRG1 deficiency can be observed in a few patients with non-small cell lung cancer (NSCLC). We aimed to compare the clinicopathological, immunohistochemical and prognostic features of SMARCA4-deficient NSCLC (SMARCA4-dNSCLC) with those of thoracic SMARCA4-UT. Methods Patients with BRG1-deficient tumors in the lung or thorax were enrolled in the study from the Department of Pathology of West China Hospital, Sichuan University, from January 2014 to June 2022. We retrospectively collected the clinicopathological and immunohistochemical features and outcomes of these patients. Results Seventy-two patients had tumors in the lung or thorax with BRG1-deficient expression, including 52 patients with SMARCA4-dNSCLC and 20 patients with thoracic SMARCA4-UT. Among the patients with SMARCA4-dNSCLC, 98.1% were male, 85.7% were smokers, and 79.5% (35/44) had tumor-node-metas­tasis (TNM) III-IV tumors. Among the patients with thoracic SMARCA4-UT, all were males who smoked, and 93.75% (15/16) had TNM III-IV tumors. Pure solid architecture and necrosis were the predominant pathological features. Rhabdoid morphology was observed in some SMARCA4-dNSCLCs (10/52, 19.2%) and thoracic SMARCA4-UTs (11/20, 55%). In most patients with thoracic SMARCA4-UT, the tumors exhibited scattered weak expression or negative expression of epithelial markers, and positive expression of CD34 and Syn. Overall survival (OS) and progression-free survival (PFS) were not significantly different between patients with SMARCA4-dNSCLC and patients with thoracic SMARCA4-UT (p = 0.63 and p = 0.20, respectively). Conclusions Thoracic SMARCA4-DTs include SMARCA4-dNSCLC and thoracic SMARCA4-UT. Both have overlapping clinicopathological features and poor prognosis. We hypothesize that thoracic SMARCA4-UT may be the undifferentiated or dedifferentiated form of SMARCA4-dNSCLC. However, further studies with larger cohorts and longer follow-up periods are needed.

Recently, the fifth edition of the WHO classification recognized the thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) as a separate entity from conventional non-small cell lung cancer with SMARCA4 deficiency because of the different clinicopathological characteristics of these two diseases. SMARCA4-UT mainly occurs in young to middle-aged adults and involves a large mass compressing the tissues surrounding the mediastinum and lung parenchyma. Unfortunately, SMARCA4-UT shows a high probability of recurrence after upfront surgery as well as radiotherapy resistance; moreover, chemotherapy has low efficacy. Moreover, given the recent classification of SMARCA4-UT, no data concerning specific clinical trials are currently available. However, several case reports show immunotherapy efficacy in patients with this disease not only in a metastatic setting but also in a neoadjuvant manner, supporting the development of clinical trials. In addition, preclinical data and initial clinical experiences suggest that inhibiting pathways such as CDK4/6, AURKA, ATR, and EZH2 may be a promising therapeutic approach to SMARCA4-UT.

Rationale: SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently reported rare malignancy that can rapidly metastasize to tissues and organs throughout the body. The tumor is characterized by a lower response to platinum-based chemotherapy. More regrettably, the mean survival time of patients with this disease after diagnosis is only 4 to 7 months. Patient concerns: A 58-year-old man was admitted to a hospital for fatigue, sudden syncope, and a mass-like shadow of his left upper lobe demonstrated by a pulmonary computed tomographic. Based on his subsequent clinical and pathological features, he was highly suspected of SMARCA4-UT. Diagnoses: Combined with next-generation sequencing genetic testing and immunohistochemical examination results, the patient was diagnosed with SMARCA4-UT. Interventions: The patient received a left upper lobectomy and lymph node dissection, four-course chemotherapy divided into 8 sessions with the use of paclitaxel simply, and a proper post-discharge self-care. Outcomes: The patient’s operation and chemotherapy were all successful and he maintained a high quality of life after surgery that far exceeded his predicted survival. Lessons: Early diagnosis, higher education level, attention to the disease and complications, reducing chemotherapy damage, adequate nutrient intake, relieving symptoms, controlling depression, and maintaining immunity and the ability to perform activities of daily living may all be the positive factors that can prolong the survival of patients with SMARCA4-UT.

AbstractThoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently described smoking-related malignancy. The pathogenesis of SMARCA4-UT is the mutational inactivation and loss of expression of a subunit encoding the mammalian switch/sucrose nonfermenting ATPase-dependent chromatin remodeling complex (which can be mobilized using adenosine triphosphate hydrolysis nucleosomes and regulate other cellular processes including development, differentiation, proliferation, and apoptosis), in particular SMARCA4 and SMARCA2. The dynamic activity of this complex plays an important role in regulating the activation and repression of gene expression programs. SMARCA4-UT exhibits morphological features similar to the malignant rhabdoid tumor (MRT), small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT), and INI1-deficient tumor, but SMARCA4-UT differs from SCCOHT and MRT from a genomic perspective. SMARCA4-UT mainly involves the mediastinum and lung parenchyma, and appears as a large infiltrative mass that easily compresses surrounding tissues. At present, chemotherapy is a common treatment, but its efficacy is not clear. Moreover, the inhibitor of the enhancer of zeste homolog 2 showed promising efficacy in some patients with SMARCA4-UT. This study aimed to review the clinical characteristics, diagnosis, treatment, and prognosis of SMARCA4-UT.

Abstract Background Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. Materials and Methods Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non–small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. Results Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. Conclusion SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.

Abstract Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare malignant disease. We present the case of a 56-year-old woman with thoracic SMARCA4-UT presenting as a mediastinal mass who underwent 68Ga-DOTA-FAPI-04 PET/CT imaging. Intense 68Ga-DOTA-FAPI-04 uptake was observed in the primary tumor and lymph node metastases. After 7 cycles of immune checkpoint inhibitor plus chemotherapy, the patient underwent mediastinal mass resection, and postoperative pathology confirmed a complete pathologic response. This case may provide valuable insights into the diagnosis and monitoring of the treatment response of thoracic SMARCA4-UT.

Context Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently described aggressive neoplasm of young smokers defined by SMARCA4 inactivating mutations and characterized by cells with rhabdoid morphology, high mitotic activity, and abundant necrosis. Objective Describe and compare 3 unusual presentations of SMARCA4-UT in older adults, including one presenting as a metastatic lesion mimicking a primary bone sarcoma. Discuss the molecular characteristics of SMARCA4-UT and their relationship to nonsmall-cell lung carcinomas with SMARCA4. Design Three patients with SMARCA4-UTs were identified utilizing a natural language search in CoPath. hematoxylin and eosin sections from all patients as well as Papanicolaou-stained slides and Diff-Quik-stained slides for the first patient were examined. A broad range of immunostains, including BRG1/SMARCA4, were evaluated. Molecular testing was performed via next-generation sequencing. Results The 3 patients were aged 58, 70, and 70 years. All had a significant smoking history. The first patient presented with an iliac bone mass and mediastinal lymphadenopathy, the second with mediastinal adenopathy, and the third with a paratracheal mass. All 3 tumors showed a diffuse proliferation of pleomorphic, rhabdoid cells with high mitotic activity and tumor necrosis. SMARCA4 was lost in all 3 tumors by immunohistochemistry. Molecular testing revealed SMARCA4 alterations in the first 2. Conclusions Thoracic SMARCA4-UT should be considered in the differential diagnosis of pleomorphic rhabdoid tumors in older adults with a smoking history. Although most present as lung and/or mediastinal masses, they may occasionally present as a metastasis and mimic an undifferentiated sarcoma, representing a potential diagnostic pitfall.

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is an extremely rare and poor-prognosis malignancy, which has recently been noted as a subtype of lung tumors. We presented a case of SMARCA4-UT in a 50-year-old man with progressively worsening respiratory failure. The tumor was the first reported to involve pulmonary artery, and 90% of tumor cells expressed programmed cell death ligand 1 (PD-L1). High tumor mutational burden (TMB, 23.93/Mb) and mutations in SMARCA4 were detected. It is the first reported case to receive Tislelizumab monotherapy with considerable improvement in clinical condition and no adverse events. As a result of our case, we highlight the importance of recognizing SMARCA4-UT as an individual entity, as well as the efficacy of immune checkpoint inhibitor therapy, particularly in patients with high levels of TMB and PD-L1 expression.

Abstract Small cell lung carcinoma (SCLC) cell lines have been widely utilized as a preclinical model of this highly aggressive disease. However, since their creation decades ago, novel tumor entities have been defined that may clinicopathologically mimic SCLC, which notably includes thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Multi-omic reassessment of the presumed SCLC cell lines with high YAP1 expression reveals that nearly all of these tumors represent unsuspected SMARCA4-UT.

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs), recently recognized as a rare malignancy described in the 5th edition of the World Health Organization Classification of Tumors, are characterized by an inactivating mutation in SMARCA4, most commonly found in the mediastinum of male smokers. Despite the aggressive nature and poor prognosis associated with these tumors, which have a median survival time of approximately 4-7 months, no standardized treatment guidelines are currently established. There are currently no reported cases of extended progression-free survival (PFS) in SMARCA4-UT patients treated with surgery and immunotherapy. Here, we report the clinical features and genomic information of a SMARCA4-UT case in which the patient responded significantly to a combination therapy involving surgery, immunotherapy, and amlotinib. A 56-year-old male non-smoker presented with a mass in the superior lobe of left lung and left hilar adenopathy. A left upper lobectomy and lymphadenectomy were performed, and postoperative pathology confirmed that the tumor was Thoracic SMARCA4-UT. The patient subsequently received chemotherapy with pemetrexed and carboplatin. Five months post-operation, the disease progressed with left adrenal metastasis and mediastinal adenopathy. An adrenalectomy was performed, followed by whole exon sequencing (WES). SMARCA4, SMARCA2 and SMARCA1 gene mutations were detected in this case. Given a tumor proportion score (TPS) of 60% for programmed death-ligand 1(22C3)immunoexpression and high TMB(361.32 muts/Mb), a combination of Pembrolizumab plus anlotinib was initiated as a second-line approach. After 46 cycles, the patient demonstrated no disease progression with a PR lasting 31 months and long progression-free survival(PFS) of 43 months. The lung tumor was initially detected in September 2020, and the patient remained alive at the latest follow-up in November 2024. This case offers a long-term follow-up of the effectiveness and safety of combining pembrolizumab and anlotinib in advanced SMARCA4-UT, and substantiates the role of long-term immunotherapy in preventing radiographic/clinical recurrence following surgery. This case illustrates new potential efficacy of immunotherapy in combination with surgery as a treatment approach of SMARCA4-UT.

Ce travail de thèse s’articule autour de trois projets indépendants dont le but est de mieux caractériser trois tumeurs mésenchymateuses grâce à une approche multi-omique intégrative.Les tumeurs thoraciques indifférenciées SMARCA4-déficientes (SMARCA4-UT), initialement « sarcomes » semblaient répondre aux inhibiteurs de point de contrôle immunitaire (ICIs) comme d’autres tumeurs SWI/SNF déficientes, sans qu’aucune caractérisation de leur microenvironnement tumoral (TME) ne soit faite pour le comprendre. Grâce à des immunomarquages et à une analyse transcriptomique, nous avons mis en évidence un TME désertique avec une efficacité limitée des ICIs, en lien avec la cellule d’origine. Les tumeurs des cellules épithélioïdes périvasculaires (PEComes) forment un ensemble hétérogène de tumeurs coexprimant des marqueurs mélanocytaires et musculaires lisses pour lesquelles deux types génomiques se distinguent. Grâce à notre analyse, nous avons démontré qu’il existait d’autres réarrangements que ceux impliquant TFE3 et qu’il existait une classification transcriptomique pronostique de quatre sous types de PEComes, chacun étant enrichi d’un profil génomique et présentant des vulnérabilités différentes sur le plan thérapeutique. Les tumeurs desmoïdes (TDs) sont des tumeurs bénignes localement agressives dont l’hétérogénéité dans l’évolution tumorale est peu comprise. Grâce à notre analyse, nous avons mis en évidence que plus de 50% des TDs avaient des mutations dans un des gènes remodelant la chromatine et que parmi les deux sous-types transcriptomiques identifiés, le type immuno-myogénique doté d’un programme transcriptomique proche de celui des muscles, activait les voies de l’immunité évoquant un potentiel thérapeutique des ICIs
This thesis work takes the form of three independent projects aimed at better characterizing three mesenchymal tumors through an integrative multi-omics approach.The thoracic undifferentiated SMARCA4-deficient tumors (SMARCA4-UT), initially classified as "sarcomas," appeared to respond to immune checkpoint inhibitors (ICIs) similarly to other SWI/SNF-deficient tumors, despite no characterization of their tumor microenvironment (TME) being done to understand this response. Through immunostaining and transcriptomic analysis, we highlighted a desert-like TME with limited ICI efficacy, linked to the tumor’s cell of origin. Perivascular epithelioid cell tumors (PEComas) form a heterogeneous group of tumors co-expressing melanocytic and smooth muscle markers, with two distinct molecular types identified. Our analysis demonstrated that there are additional rearrangements beyond those involving TFE3 and provided a prognostic transcriptomic classification of four PEComa subtypes, each enriched with a unique genomic profile and presenting different therapeutic vulnerabilities. Desmoid tumors (TDs) are benign, locally aggressive tumors with poorly understood heterogeneity in tumor evolution. Our analyses revealed that more than 50% of TDs had mutations in chromatin remodeling genes and that among the two identified transcriptomic subtypes, the immuno-myogenic subtype, with a transcriptomic program similar to muscles, activated immune pathways suggesting a potential therapeutic benefit from ICIs