ABSTRACT
Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.
Subject(s)
Micrognathism , Promoter Regions, Genetic , Repressor Proteins , Rhabdoid Tumor , SMARCB1 Protein , Transcription Factors , Animals , Humans , Male , Mice , Abnormalities, Multiple , Cell Line, Tumor , Chromatin/metabolism , Chromatin Assembly and Disassembly , Chromosomal Proteins, Non-Histone/metabolism , Chromosomal Proteins, Non-Histone/genetics , CRISPR-Cas Systems , Face/abnormalities , Foot Deformities, Congenital/genetics , Foot Deformities, Congenital/metabolism , Hand Deformities, Congenital , Intellectual Disability/genetics , Intellectual Disability/metabolism , Micrognathism/genetics , Micrognathism/metabolism , Mutation , Neck/abnormalities , Promoter Regions, Genetic/genetics , Repressor Proteins/metabolism , Repressor Proteins/genetics , Rhabdoid Tumor/genetics , Rhabdoid Tumor/metabolism , Rhabdoid Tumor/pathology , SMARCB1 Protein/metabolism , SMARCB1 Protein/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Transcription, GeneticSubject(s)
Brain Neoplasms , RNA-Binding Proteins , Humans , Male , Female , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Brain Neoplasms/genetics , Child, Preschool , Retrospective Studies , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Glial Fibrillary Acidic Protein/metabolism , Glial Fibrillary Acidic Protein/genetics , Nestin/metabolism , Nestin/genetics , Parietal Lobe/pathology , Parietal Lobe/metabolism , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Chromosomal Proteins, Non-Histone/metabolism , Chromosomal Proteins, Non-Histone/genetics , Brain Stem Neoplasms/pathology , Brain Stem Neoplasms/genetics , Brain Stem Neoplasms/metabolism , Brain Stem Neoplasms/surgery , Transcription Factors/metabolism , Transcription Factors/genetics , SMARCB1 Protein/metabolism , SMARCB1 Protein/genetics , Frontal Lobe/pathology , Frontal Lobe/metabolism , Rosette Formation , Follow-Up Studies , Ki-67 Antigen/metabolism , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/geneticsABSTRACT
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) constituting 85% of cases. Among NSCLCs, squamous cell carcinoma (SqCC) is strongly associated with smoking. However, lung cancer in never smokers (LCINS) represents approximately 25% of lung cancer cases globally and shows increasing incidence, particularly in East Asia. LCINS-SqCC is less well-characterized, especially regarding its genomic alterations and their impact on clinical outcomes. We conducted a retrospective analysis over a 20-year period (July 2003-July 2023) at two major tertiary centers in the UK. The cohort included 59 patients with LCINS-SqCC who underwent radical surgical resection. Data collected included demographic information, comorbidities, histopathological details, and outcome metrics such as disease-free and overall survival. Molecular sequencing of tumor specimens was performed to identify genomic aberrations. The cohort had a median age of 71 years (IQR 62-77) and a median BMI of 25.4 (IQR 22.8-27.8), with a slight male predominance (53%). The majority of patients (93%) had a preoperative MRC of 1-2. Recurrent disease was observed in 23 patients (39%), and 32 patients (54%) had died at a median follow-up of 3 years. Median disease-free survival was 545 days (IQR 132-1496), and overall survival was 888 days (IQR 443-2071). Preoperative creatinine levels were higher in patients who experienced recurrence (p = 0.037). Molecular analysis identified biallelic SMARCB1 loss in two younger patients, associated with rapid disease progression despite R0 resection. These patients' tumors were PDL1-negative, TTF-1-negative, and positive for cytokeratin, CD56, and p40. SMARCB1-deficient SqCC in never smokers represents a highly aggressive variant with poor disease-free survival, highlighting the importance of integrating advanced molecular diagnostics in clinical practice. This study underscores the necessity for personalized treatment strategies, including targeted therapies such as EZH2 inhibitors and immune checkpoint blockade, to address the unique molecular pathways in SMARCB1-deficient cancers. Further clinical trials are essential to optimize therapeutic approaches for this challenging subgroup of lung cancer.
Subject(s)
Carcinoma, Squamous Cell , Lung Neoplasms , SMARCB1 Protein , Humans , Male , Female , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Aged , Middle Aged , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Retrospective Studies , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Non-Smokers , Biomarkers, Tumor/geneticsABSTRACT
SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, is the causative gene of rhabdoid tumors and epithelioid sarcomas. Here, we identify a paralog pair of CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers by using a dual siRNA screening method based on the "simultaneous inhibition of a paralog pair" concept. Treatment with CBP/p300 dual inhibitors suppresses growth of cell lines and tumor xenografts derived from SMARCB1-deficient cells but not from SMARCB1-proficient cells. SMARCB1-containing SWI/SNF complexes localize with H3K27me3 and its methyltransferase EZH2 at the promotor region of the KREMEN2 locus, resulting in transcriptional downregulation of KREMEN2. By contrast, SMARCB1 deficiency leads to localization of H3K27ac, and recruitment of its acetyltransferases CBP and p300, at the KREMEN2 locus, resulting in transcriptional upregulation of KREMEN2, which cooperates with the SMARCA1 chromatin remodeling complex. Simultaneous inhibition of CBP/p300 leads to transcriptional downregulation of KREMEN2, followed by apoptosis induction via monomerization of KREMEN1 due to a failure to interact with KREMEN2, which suppresses anti-apoptotic signaling pathways. Taken together, our findings indicate that simultaneous inhibitors of CBP/p300 could be promising therapeutic agents for SMARCB1-deficient cancers.
Subject(s)
Gene Expression Regulation, Neoplastic , SMARCB1 Protein , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Humans , Animals , Cell Line, Tumor , Mice , p300-CBP Transcription Factors/metabolism , p300-CBP Transcription Factors/genetics , E1A-Associated p300 Protein/metabolism , E1A-Associated p300 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Chromatin Assembly and Disassembly/genetics , Mice, Nude , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Xenograft Model Antitumor Assays , Promoter Regions, Genetic/genetics , Cell Proliferation/genetics , Cell Proliferation/drug effects , Rhabdoid Tumor/genetics , Rhabdoid Tumor/metabolism , Rhabdoid Tumor/pathologyABSTRACT
Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.
Subject(s)
Multiprotein Complexes , Mutation , Neoplasms , SMARCB1 Protein , Animals , Female , Humans , Male , Mice , Cell Line, Tumor , CRISPR-Cas Systems , Gene Editing , Neoplasms/genetics , Neoplasms/metabolism , SMARCB1 Protein/deficiency , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Tumor Suppressor Proteins/deficiency , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Multiprotein Complexes/chemistry , Multiprotein Complexes/metabolism , Proteolysis , Ubiquitin/metabolismABSTRACT
SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces tumor growth in SMARCB1 KO orthotopic cell line-derived xenografts and a SMARCB1-deficient patient derived xenograft model. We have identified a gene signature generated from SMARCB1 KO tumors that predicts SMARCB1 deficiency in patients. Overall, these findings support the clinical evaluation of STAT3 inhibitors for the treatment of SMARCB1-deficient bladder cancer.
Subject(s)
Interleukin-6 , Urinary Bladder Neoplasms , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Signal Transduction/genetics , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Urinary Bladder Neoplasms/genetics , Cell Line, Tumor , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolismABSTRACT
Pathogenic variants (mutations) and other molecular events involving subunits of the SWItch/Sucrose Non-Fermentable chromatin remodelling complex are common in a wide variety of malignancies. Many of these neoplasms are characterized by undifferentiated morphology. They arise at a variety of sites in the female genital tract but have rarely been reported in the uterine cervix. We report 2 primary cervical neoplasms arising in young women (ages 28 and 29 yr) exhibiting loss of nuclear immunoreactivity with SMARCB1 (INI1). In one case, which had a mixture of epithelioid and spindle cells, molecular studies revealed no SMARCB1 pathogenic variant, but showed a SPECCL1::NTRK 3 fusion, in keeping with an NTRK fusion sarcoma. The second case exhibited rhabdoid morphology and molecular testing confirmed a SMARCB1 pathogenic variant (c.425 T>G:p.(Leu142Ter) which, interpreted in conjunction with the morphology and immunohistochemistry, resulted in classification as a proximal-type epithelioid sarcoma. To our knowledge, this is the first reported cervical neoplasm exhibiting a SMARCB1 pathogenic variant and the first NTRK fusion sarcoma showing SMARCB1 protein loss. We discuss the diagnostic challenges and complexities of the molecular findings.
Subject(s)
SMARCB1 Protein , Uterine Cervical Neoplasms , Humans , Female , SMARCB1 Protein/genetics , SMARCB1 Protein/deficiency , SMARCB1 Protein/metabolism , Adult , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/diagnosis , Immunohistochemistry , Cervix Uteri/pathology , Sarcoma/genetics , Sarcoma/pathology , Sarcoma/diagnosis , Oncogene Proteins, Fusion/genetics , Receptor, trkCABSTRACT
BACKGROUND: Despite major advancements, effective treatment for patients with SMARCB1-deficient cancers has remained elusive. Here, we report the first case of a SMARCB1-deficient undifferentiated carcinoma in the rectum expressing high PD-L1 and responding to a PD-1 inhibitor, as well as with low tumor mutation burden (TMB), proficient mismatch repair (MMR) and BRAF V600E mutation. CASE PRESENTATION: A 35-year-old man visited our hospital complaining of increased defecation frequency, bloody stools and weight loss of 3 kg for one month. Colonoscopy revealed an ulcerated and irregular mass approximately 8-12 cm from the anus. Surgical resection was performed. Histopathological findings revealed that the tumor cells had poor connectivity with each other; each cell had eosinophilic cytoplasm and a polymorphic nucleus. Brisk mitotic activity and necrosis were frequently observed in the tumor cells. Immunohistochemical examination showed that the tumor cells were negative for SMARCB1. The tumor proportion score (TPS) of PD-L1 (22C3) expression was 95%, and the combined positive score (CPS) was 100; the tumor was mismatch repair (MMR) proficient. Next-generation sequencing showed a low tumor mutation burden (TMB), as well as the BRAF V600E mutation. The final diagnosis was SMARCB1-deficient undifferentiated carcinoma. Chemotherapy was useless in this case. His tumor recurred during chemotherapy, and he then received targeted therapy with tirelizumab, an inhibitor of PD-1. At present, his general condition is good. A recent computed tomography (CT) scan showed that the tumor had disappeared, indicating that the immunotherapy was effective. Astonishingly, his most recent follow-up was in August, and his condition continued to improve with the tumor has disappeared. CONCLUSION: SMARCB1deficient undifferentiated carcinoma in the rectum is extremely rare, and it has aggressive histological malignancy and poor progression. The observed response to PD-1 inhibitors suggests a role for prospective use of SMARCB1 alterations as a predictive marker for immune checkpoint blockade.
Subject(s)
Carcinoma , Immune Checkpoint Inhibitors , Male , Humans , Adult , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , B7-H1 Antigen/metabolism , DNA Mismatch Repair/genetics , Mutation , Neoplasm Recurrence, Local , Carcinoma/pathology , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolismABSTRACT
Epithelioid sarcoma (EpS) is an ultra-rare malignant soft-tissue cancer mostly affecting adolescents and young adults. EpS often exhibits an unfavorable clinical course with fatal outcome in â¼50% of cases despite aggressive multimodal therapies combining surgery, chemotherapy, and irradiation. EpS is traditionally classified in a more common, less aggressive distal (classic) type and a rarer aggressive proximal type. Both subtypes are characterized by a loss of nuclear INI1 expression, most often following homozygous deletion of its encoding gene, SMARCB1-a core subunit of the SWI/SNF chromatin remodeling complex. In 2020, the EZH2 inhibitor tazemetostat was the first targeted therapy approved for EpS, raising new hopes. Still, the vast majority of patients did not benefit from this drug or relapsed rapidly. Further, other recent therapeutic modalities, including immunotherapy, are only effective in a fraction of patients. Thus, novel strategies, specifically targeted to EpS, are urgently needed. To accelerate translational research on EpS and eventually boost the discovery and development of new diagnostic tools and therapeutic options, a vibrant translational research community has formed in past years and held two international EpS digital expert meetings in 2021 and 2023. This review summarizes our current understanding of EpS from the translational research perspective and points to innovative research directions to address the most pressing questions in the field, as defined by expert consensus and patient advocacy groups.
Subject(s)
Sarcoma , Transcription Factors , Adolescent , Young Adult , Humans , Transcription Factors/genetics , DNA-Binding Proteins/genetics , Chromosomal Proteins, Non-Histone/genetics , Homozygote , Consensus , Sequence Deletion , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Sarcoma/diagnosis , Sarcoma/genetics , Sarcoma/therapyABSTRACT
BACKGROUND: SMARCB1, also known as INI1, is a member of a large protein complex involved in chromatin remodeling and thus the regulation of gene expression. It is located on chromosome 22q11.2. SMARCB1 tumors have been found in various locations, including the sinonasal region, gastrointestinal tract, central nervous system (in atypical teratoid and rhabdoid tumors), and perirenal region (in malignant rhabdoid tumors) in both adults and children. CASE PRESENTATION: We describe here the first case in the literature of an INI1-deficient neck carcinoma without a primary tumor managed with surgical therapy and neck dissection in a young Caucasian woman of 29 years old, followed by chemotherapy before radiotherapy, with regional control after 18 months of follow-up. Histologic analysis showed an undifferentiated carcinoma without glandular or epidermoid differentiation. Biomolecular analysis of the tumor revealed a homozygous deletion of the SMARCB1 gene on RNA sequencing. CONCLUSION: Research of INI1 deletion should be performed for undifferentiated carcinoma of young patients because of possibilities of molecular therapies such as autophagy inhibitors or proteasome inhibitors could be used in clinical trials.
Subject(s)
Carcinoma , Head and Neck Neoplasms , Rhabdoid Tumor , Adult , Child , Female , Humans , Rhabdoid Tumor/genetics , Homozygote , Sequence Deletion , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Carcinoma/genetics , Carcinoma/pathology , Head and Neck Neoplasms/genetics , Biomarkers, Tumor/geneticsABSTRACT
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Extensive rhabdoid morphology in ACC has been described recently in very few cases. The proportion of rhabdoid morphology and the role of SMARCB1/ INI1 expression in these tumor cells to diagnose the specific variant is not described in the literature. We reviewed the clinicopathological features of nine cases of adrenocortical neoplasm. Out of which, three cases of ACC showed predominant rhabdoid morphology. Large discohesive cells with abundant cytoplasm containing eosinophilic inclusions, eccentric vesicular nucleus, and prominent nucleoli. INI1 immunostain was retained in all cases. We reported the rhabdoid variant of ACC, a novel entity, and its diagnostic approach from their histological mimickers. Identifying more cases of this entity will help to clearly understand the pathogenesis, biologic behaviour, and any specific molecular alterations in the future.
Subject(s)
Adrenal Cortex Neoplasms , Adrenocortical Carcinoma , Rhabdoid Tumor , Humans , Adrenocortical Carcinoma/diagnosis , Rhabdoid Tumor/diagnosis , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Adrenal Cortex Neoplasms/diagnosis , Biomarkers, Tumor/metabolismABSTRACT
Soft tissue sarcomas (STSs) are rare mesechymal malignancies characterized by distintive molecular, histological and clinical features. Many STSs are considered as predominatly epigenetic diseases due to underlying chromatin deregulation. Discovery of deregulated functional antagonism between the chromatin remodeling BRG1/BRM-associated (BAFs) and the histone modifying Polycomb repressor complexes (PRCs) has provided novel actionable targets. In epithelioid sarcoma (ES), extracranial, extrarenal malignant rhabdoid tumors (eMRTs) and synovial sarcoma (SS), the total or partial loss of the BAF core subunit SMARCB1, driven by different alterations, is associated with PRC2 deregulation and dependency on its enzymatic subunit, EZH2. In these SMARCB1-deficient STSs, aberrant EZH2 expression and/or activity emerged as a druggable vulnerability. Although preclinical investigation supported EZH2 targeting as a promising therapeutic option, clinical studies demonstrated a variable response to EZH2 inhibitors. Actually, whereas the clinical benefit recorded in ES patients prompted the FDA approval of the EZH2 inhibitor tazemetostat, the modest and sporadic responses observed in eMRT and SS patients highlighted the need to deepen mechanistic as well as pharmacological investigations to improve drug effectiveness. We summarize the current knowledge of different mechanisms driving SMARCB1 deficiency and EZH2 deregulation in ES, eMRT and SS along with preclinical and clinical studies of EZH2-targeting agents. Possible implication of the PRC2- and enzymatic-independent functions of EZH2 and of its homolog, EZH1, in the response to anti-EZH2 agents will be discussed together with combinatorial strategies under investigation to improve the efficacy of EZH2 targeting in these tumors.
Subject(s)
Sarcoma , Humans , Sarcoma/drug therapy , Sarcoma/genetics , Histones , Enzyme Inhibitors , Chromatin , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolismABSTRACT
Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.
Subject(s)
Carcinoma, Medullary , Carcinoma, Renal Cell , Ferroptosis , Kidney Neoplasms , Sickle Cell Trait , Humans , Kidney Neoplasms/pathology , Carcinoma, Medullary/metabolism , Carcinoma, Renal Cell/pathology , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Repressor Proteins , Homeodomain ProteinsABSTRACT
ABSTRACT: Epithelioid sarcoma (ES) is a distinctive malignant mesenchymal neoplasm with atypical epithelioid cells palisading around a central zone of necrosis. ES is a rare entity even in soft tissue pathology. Immunohistochemically, tumors usually show diffuse epithelial membrane antigen and cytokeratin expression and loss of nuclear INI1 (SMARCB1) expression. Here, we report a case of a 64-year-old man with ES arising in the left conchal bowl. Given the clinical presentation including patient's age, sun-exposed area of skin, and slow-growing, asymptomatic, small pink pearly papule, this patient was initially misdiagnosed with basal cell carcinoma clinically and treated with topical imiquimod at an outside facility. The lesion continued to grow and eventually became symptomatic despite the treatment after which biopsy was obtained. Despite the unusual anatomic site and the patient's age, the microscopic and immunohistochemical findings were characteristic of conventional-type ES. Our case shows that ES can arise in rare locations and in older adults where it may be more easily misdiagnosed clinically and pathologically as a nonmelanoma skin cancer.
Subject(s)
Sarcoma , Skin Neoplasms , Male , Humans , Aged , Middle Aged , Biomarkers, Tumor/metabolism , SMARCB1 Protein/metabolism , Sarcoma/pathology , Skin Neoplasms/drug therapy , Biopsy , Keratins/metabolismABSTRACT
Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Sickle Cell Trait , Animals , Humans , Mice , Carcinoma, Renal Cell/pathology , Hypoxia/genetics , Hypoxia/metabolism , Kidney/metabolism , Kidney Neoplasms/pathology , Sickle Cell Trait/genetics , Sickle Cell Trait/metabolism , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolismABSTRACT
The recently described SWI/SNF complex-deficient sinonasal carcinoma (SMARCB1 & SMARCA4) may exhibit a yolk sac-like morphology. Tumors with similar features (yolk sac-like histology combined with the immunohistochemical loss of SMARCB1/INI1 and/or SMARCA4/BRG1) have also been described in other sites, such as the female genital tract. In this study, we immunohistochemically assessed SMARCB1/INI1 and SMARCA4/BRG1 expression to evaluate if these proteins could be involved in the pathogenesis of testicular yolk sac tumors of postpubertal type (YSTpt). Specifically, we analyzed a retrospective case series comprising pure YSTpt and mixed germ cell tumors of the testis (GCTT) with YSTpt components. In the present study, no testicular YSTpt showed loss of SMARCB1/INI1 (0/24, 0%) or SMARCA4/BRG1 (0/24, 0%). However, testicular choriocarcinoma (CHC) and isolated syncytiotrophoblast cells (iSTCs) demonstrated abnormal staining patterns for SMARCA4/BRG1 [CHC: 4/4 (100%); iSTCs: 12/12 (100%), respectively], including focal or diffuse loss of expression in a subset of cases. The results of our study suggest that functional loss of SMARCA4/BRG1 represents a recurrent event that may be relevant for the pathogenesis of a subset of testicular CHC.
Subject(s)
Carcinoma , Choriocarcinoma , Endodermal Sinus Tumor , Male , Female , Humans , Retrospective Studies , Biomarkers, Tumor , SMARCB1 Protein/metabolism , Carcinoma/pathology , DNA Helicases , Nuclear Proteins , Transcription FactorsABSTRACT
Undifferentiated/dedifferentiated endometrial carcinomas (UDEC and DDEC) are rare, aggressive uterine neoplasms, with no specific line of differentiation. A significant proportion of these cases feature mutations of SWI/SNF chromatin remodeling complex members, including ARID1A, SMARCA4, and SMARCB1 genes. To study these entities more comprehensively, we identified 10 UDECs and 10 DDECs from our pathology archives, obtained clinicopathologic findings and follow-up data, and performed immunohistochemical studies for ARID1A, BRG1 (SMARCA4), and INI1 (SMARCB1) proteins. In addition, we successfully conducted targeted next-generation sequencing for 23 samples, including 7 UDECs, and 7 undifferentiated and 9 well/moderately-differentiated components of DDECs. Cases consisted of 18 hysterectomies and 2 curettage/biopsy specimens. Patient age ranged from 47 to 77 years (median, 59 years), with a median tumor size of 8.0 cm (range, 2.5-13.0 cm). All cases demonstrated lymphovascular invasion and the majority (13/20) were FIGO stage III-IV. By immunohistochemistry, ARID1A loss was observed in 15 cases, BRG1 loss in 4, and all cases had intact INI1 expression. A trend for enrichment of the undifferentiated component of DDECs for ARID1A loss was seen, although not statistically significant. Sequencing revealed frequent pathogenic mutations in PTEN, PIK3CA, ARID1A, CTNNB1, and RNF43, a recurrent MAX pathogenic mutation, and MYC and 12p copy number gains. In DDECs, the undifferentiated component featured a higher tumor mutational burden compared to the well/moderately-differentiated component; however, the mutational landscape largely overlapped. Overall, our study provides deep insights into the mutational landscape of UDEC/DDEC, SWI/SNF chromatin remodeling complex member status, and their potential relationships with tumor features.
Subject(s)
Carcinoma , Endometrial Neoplasms , Female , Humans , Middle Aged , Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Endometrial Neoplasms/pathology , Immunohistochemistry , Carcinoma/pathology , High-Throughput Nucleotide Sequencing , DNA Helicases/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , DNA-Binding Proteins/geneticsABSTRACT
Loss of the gene SMARCB1 drives the development of malignant rhabdoid tumors, epithelioid sarcomas, and other malignancies. The SMARCB1 protein is a core component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) family of chromatin remodeling complexes, which are important regulators of gene expression and cell differentiation. Here, we use CRISPR-Cas9 to create germline smarcb1 loss of function in zebrafish. We demonstrate that the combination of smarcb1 deficiency with mutant p53 results in the development of epithelioid sarcomas, angiosarcomas, and carcinomas of the thyroid and colon. Although human epithelioid sarcomas do not frequently harbor p53 mutations, smarcb1-deficient tumors in zebrafish were only observed following disruption of p53, indicating that p53 signaling in human tumors might be attenuated through alternative mechanisms, such as MDM2-mediated proteasomal degradation of p53. To leverage this possibility for the treatment of human epithelioid sarcoma, we tested small molecule-mediated disruption of the p53-MDM2 interaction, which stabilized p53 protein leading to p53-pathway reactivation, cell-cycle arrest, and increased apoptosis. Moreover, we found that MDM2 inhibition and the topoisomerase II inhibitor doxorubicin synergize in targeting epithelioid sarcoma cell viability. This could be especially relevant for patients with epithelioid sarcoma because doxorubicin represents the current gold standard for their clinical treatment. Our results therefore warrant reactivating p53 protein in SMARCB1-deficient, p53-wildtype epithelioid sarcomas using combined doxorubicin and MDM2 inhibitor therapy.
Subject(s)
Rhabdoid Tumor , Sarcoma , Animals , Humans , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Zebrafish/metabolism , Tumor Suppressor Protein p53/genetics , DNA-Binding Proteins/metabolism , Chromosomal Proteins, Non-Histone/genetics , Sarcoma/drug therapy , Sarcoma/genetics , Sarcoma/metabolism , Rhabdoid Tumor/genetics , Doxorubicin/pharmacology , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolismABSTRACT
Epithelioid sarcoma (ES) is a very rare and aggressive mesenchymal tumor of unclear origin and uncertain lineage characterized by a prevalent epithelioid morphology. The only recurrent genetic alteration reported in ES as yet is the functional inactivation of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), a key component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes. How SMARCB1 deficiency dictates the clinicopathological characteristics of ES and what other molecular defects concur to its malignant progression is still poorly understood. This review summarizes the recent findings about ES pathobiology, including defects in chromatin remodeling and other signaling pathways and their role as therapeutic vulnerabilities.
Subject(s)
DNA-Binding Proteins , Sarcoma , Chromatin Assembly and Disassembly , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , DNA-Binding Proteins/metabolism , Humans , SMARCB1 Protein/genetics , SMARCB1 Protein/metabolism , Sarcoma/pathology , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
The switch/sucrose-non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeling complex that plays important roles in DNA repair, transcription and cell differentiation. This complex consists of multiple subunits and is of particular interest in thoracic malignancies due to frequent subunit alteration of SMARCA4 (BRG1). Much less is known about SMARCB1 (INI1) deficient intrathoracic neoplasms, which are rare, often misclassified and understudied. In a retrospective analysis of 1479 intrathoracic malignant neoplasms using immunohistochemistry for INI1 (SMARCB1) on tissue micro arrays (TMA) and a search through our hospital sarcoma database, we identified in total nine intrathoracic, INI1 deficient cases (n = 9). We characterized these cases further by additional immunohistochemistry, broad targeted genomic analysis, methylation profiling and correlated them with clinical and radiological data. This showed that genomic SMARCB1 together with tumor suppressor alterations drive tumorigenesis in some of these cases, rather than epigenetic changes such as DNA methylation. A proper diagnostic classification, however, remains challenging. Intrathoracic tumors with loss or alteration of SMARCB1 (INI1) are highly aggressive and remain often underdiagnosed due to their rarity, which leads to false diagnostic interpretations. A better understanding of these tumors and proper diagnosis is important for better patient care as clinical trials and more targeted therapeutic options are emerging.