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Seminars in Diagnostic Pathology May 2021The SWItch Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex is a large multi-subunit protein assembly that orchestrates chromatin compaction and... (Review)
Review
The SWItch Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex is a large multi-subunit protein assembly that orchestrates chromatin compaction and accessibility for gene transcription in an ATP-dependent manner. As a key epigenetic regulator, the SWI/SNF complex coordinates gene expression, cell proliferation and differentiation, and its biologic functions, in part, antagonize the polycomb repressive complex 2. The mammalian SWI/SNF complex consists of 15 subunits encoded by 29 genes, some of which are recurrently mutated in human cancers, in the germline or sporadic setting. Most SWI/SNF-deficient tumors share common "rhabdoid" cytomorphology. SMARCB1 (INI1) is the subunit most frequently inactivated in soft tissue neoplasms. Specifically, SMARCB1 deficiency is observed as the genetic hallmark in virtually all malignant rhabdoid tumors, and most cases of epithelioid sarcoma and poorly differentiated chordoma. In addition, subsets of myoepithelial carcinoma (10-40%), extraskeletal myxoid chondrosarcoma (20%), epithelioid schwannoma (40%), and epithelioid malignant peripheral nerve sheath tumor (70%) demonstrate SMARCB1 loss. The gene encoding the SS18 subunit is involved in the SS18-SSX rearrangement, which is pathognomonic of synovial sarcoma and indirectly inactivates SMARCB1. Finally, undifferentiated SMARCA4-deficient thoracic sarcomas are defined by SMARCA4 subunit inactivation, leading to SMARCA4 and SMARCA2 loss. Rarely, inactivation of alternate but biologically equivalent key regulators can substitute for canonical subunit deficiency, such as SMARCA4 inactivation in cases of SMARCB1-retained epithelioid sarcoma. This review briefly highlights SWI/SNF complex biologic functions and its roles in human cancer and provides a detailed update on recent advances in soft tissue neoplasms with canonical SWI/SNF complex deficiency, correlating morphologic, genomic, and immunohistochemical findings.
Topics: Chromosomal Proteins, Non-Histone; DNA Helicases; Humans; Immunohistochemistry; Nuclear Proteins; Rhabdoid Tumor; Soft Tissue Neoplasms; Sucrose; Transcription Factors
PubMed: 32646614
DOI: 10.1053/j.semdp.2020.05.005 -
Nature Cell Biology Dec 2018Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical...
Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets.
Topics: Cell Line, Tumor; Cell Proliferation; Chromatin; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; HEK293 Cells; Humans; Mutation; Nuclear Proteins; Promoter Regions, Genetic; RNA Interference; Rhabdoid Tumor; Sarcoma, Synovial; Transcription Factors
PubMed: 30397315
DOI: 10.1038/s41556-018-0221-1 -
Journal of Clinical Oncology : Official... Apr 2020Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first...
Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333.
PURPOSE
Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT.
PATIENTS AND METHODS
Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored.
RESULTS
Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort ( < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients.
CONCLUSION
The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Infant; Infant, Newborn; Male; Prognosis; Radiotherapy, Conformal; Rhabdoid Tumor; SMARCB1 Protein; Teratoma; Young Adult
PubMed: 32105509
DOI: 10.1200/JCO.19.01776 -
Neuro-oncology May 2020Atypical teratoid/rhabdoid tumors (ATRTs) are known to exhibit molecular and clinical heterogeneity even though SMARCB1 inactivation is the sole recurrent genetic event... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atypical teratoid/rhabdoid tumors (ATRTs) are known to exhibit molecular and clinical heterogeneity even though SMARCB1 inactivation is the sole recurrent genetic event present in nearly all cases. Indeed, recent studies demonstrated 3 molecular subgroups of ATRTs that are genetically, epigenetically, and clinically distinct. As these studies included different numbers of tumors, various subgrouping techniques, and naming, an international working group sought to align previous findings and to reach a consensus on nomenclature and clinicopathological significance of ATRT subgroups.
METHODS
We integrated various methods to perform a meta-analysis on published and unpublished DNA methylation and gene expression datasets of ATRTs and associated clinicopathological data.
RESULTS
In concordance with previous studies, the analyses identified 3 main molecular subgroups of ATRTs, for which a consensus was reached to name them ATRT-TYR, ATRT-SHH, and ATRT-MYC. The ATRT-SHH subgroup exhibited further heterogeneity, segregating further into 2 subtypes associated with a predominant supratentorial (ATRT-SHH-1) or infratentorial (ATRT-SHH-2) location. For each ATRT subgroup we provide an overview of its main molecular and clinical characteristics, including SMARCB1 alterations and pathway activation.
CONCLUSIONS
The introduction of a common classification, characterization, and nomenclature of ATRT subgroups will facilitate future research and serve as a common ground for subgrouping patient samples and ATRT models, which will aid in refining subgroup-based therapies for ATRT patients.
Topics: Consensus; DNA Methylation; Humans; Neoplasms, Neuroepithelial; Rhabdoid Tumor; Teratoma
PubMed: 31889194
DOI: 10.1093/neuonc/noz235 -
Journal of the National Cancer Institute Nov 2023National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors,...
BACKGROUND
National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat.
METHODS
Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat.
RESULTS
Twenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports.
CONCLUSIONS
Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.
Topics: United States; Humans; Child; Child, Preschool; National Cancer Institute (U.S.); Rhabdoid Tumor; SMARCB1 Protein; Benzamides; DNA Helicases; Nuclear Proteins; Transcription Factors; Enhancer of Zeste Homolog 2 Protein
PubMed: 37228094
DOI: 10.1093/jnci/djad085 -
Molecular Cell Jul 2022Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of...
Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of the polycomb protein EZH2 was approved for the treatment of a sarcoma mutant in the SWI/SNF subunit SMARCB1, but resistance occurs. Here, we performed CRISPR screens in SMARCB1-mutant rhabdoid tumor cells to identify genetic contributors to SWI/SNF-polycomb antagonism and potential resistance mechanisms. We found that loss of the H3K36 methyltransferase NSD1 caused resistance to EZH2 inhibition. We show that NSD1 antagonizes polycomb via cooperation with SWI/SNF and identify co-occurrence of NSD1 inactivation in SWI/SNF-defective cancers, indicating in vivo relevance. We demonstrate that H3K36me2 itself has an essential role in the activation of polycomb target genes as inhibition of the H3K36me2 demethylase KDM2A restores the efficacy of EZH2 inhibition in SWI/SNF-deficient cells lacking NSD1. Together our data expand the mechanistic understanding of SWI/SNF and polycomb interplay and identify NSD1 as the key for coordinating this transcriptional control.
Topics: Chromatin; Enhancer of Zeste Homolog 2 Protein; F-Box Proteins; Histone-Lysine N-Methyltransferase; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Polycomb-Group Proteins; Rhabdoid Tumor; SMARCB1 Protein; Transcription Factors; Transcriptional Activation; Tumor Cells, Cultured
PubMed: 35537449
DOI: 10.1016/j.molcel.2022.04.015 -
Nature Communications Mar 2020Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and...
Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. Paediatric kidney tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug sensitivities. Using single cell RNA-sequencing and high resolution 3D imaging, we further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like cells. Our organoid biobank captures the heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterised models for basic cancer research, drug-screening and personalised medicine.
Topics: Adolescent; Biological Specimen Banks; Carcinoma, Renal Cell; Cell Culture Techniques; Child; Child, Preschool; DNA Methylation; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Genotyping Techniques; Humans; Infant; Kidney; Kidney Neoplasms; Male; Nephroma, Mesoblastic; Netherlands; Organoids; Precision Medicine; RNA-Seq; Rhabdoid Tumor; Single-Cell Analysis; Transfection; Tumor Cells, Cultured; Whole Genome Sequencing; Wilms Tumor; Young Adult
PubMed: 32161258
DOI: 10.1038/s41467-020-15155-6 -
F1000Research 2020The gene was first discovered in the mid-1990s, and since then it has been revealed that loss of function mutations in this gene result in aggressive rhabdoid tumors.... (Review)
Review
The gene was first discovered in the mid-1990s, and since then it has been revealed that loss of function mutations in this gene result in aggressive rhabdoid tumors. Recently, the term "rhabdoid tumor" has become synonymous with decreased expression. When genetic aberrations in the gene occur, the result can cause complete loss of expression, decreased expression, and mosaic expression. Although SMARCB1/INI1-deficient tumors are predominantly sarcomas, this is a diverse group of tumors with mixed phenotypes, which can often make the diagnosis challenging. Prognosis for these aggressive tumors is often poor. Moreover, refractory and relapsing progressive disease is common. As a result, accurate and timely diagnosis is imperative. Despite the gene itself and its implications in tumorigenesis being discovered over two decades ago, there is a paucity of rhabdoid tumor cases reported in the literature that detail expression. Much work remains if we hope to provide additional therapeutic strategies for patients with aggressive SMARCB1/INI1-deficient tumors.
Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Female; Humans; Male; Middle Aged; Mosaicism; Rhabdoid Tumor; SMARCB1 Protein; Young Adult
PubMed: 33796273
DOI: 10.12688/f1000research.24808.2 -
Critical Reviews in Oncogenesis 2015Rhabdoid tumor is a rare, highly aggressive malignancy that primarily affects infants and young children. These tumors typically arise in the brain and kidney, although... (Review)
Review
Rhabdoid tumor is a rare, highly aggressive malignancy that primarily affects infants and young children. These tumors typically arise in the brain and kidney, although extrarenal, non-central nervous system tumors in almost all soft-tissue sites have been described. SMARCB1 is a member of the SWI/SNF chromatin-remodeling complex and functions as a tumor suppressor in the vast majority of rhabdoid tumors. Patients with germline mutations or deletions affecting SMARCB1 are predisposed to the development of rhabdoid tumors, as well as the genetic disorder schwannomatosis. The current hypothesis is that rhabdoid tumors are driven by epigenetic dysregulation, as opposed to the alteration of a specific biologic pathway. The strategies for novel therapeutic approaches based on what is currently known about rhabdoid tumor biology are presented.
Topics: Animals; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Epigenesis, Genetic; Genetic Therapy; Humans; Rhabdoid Tumor; SMARCB1 Protein; Transcription Factors; Treatment Outcome
PubMed: 26349416
DOI: 10.1615/critrevoncog.2015013566 -
International Journal of Molecular... Jun 2022Renal medullary carcinoma (RMC) is a rare renal malignancy that has been associated with sickle hemoglobinopathies. RMC is aggressive, difficult to treat, and occurs... (Review)
Review
Renal medullary carcinoma (RMC) is a rare renal malignancy that has been associated with sickle hemoglobinopathies. RMC is aggressive, difficult to treat, and occurs primarily in adolescents and young adults of African ancestry. This cancer is driven by the loss of SMARCB1, a tumor suppressor seen in a number of primarily rare childhood cancers (e.g., rhabdoid tumor of the kidney and atypical teratoid rhabdoid tumor). Treatment options remain limited due in part to the limited knowledge of RMC biology. However, significant advances have been made in unraveling the biology of RMC, from genomics to therapeutic targets, over the past 5 years. In this review, we will present these advances and discuss what new questions exist in the field.
Topics: Adolescent; Carcinoma, Medullary; Carcinoma, Renal Cell; Child; Humans; Kidney Neoplasms; Neoplasms, Neuroepithelial; Rhabdoid Tumor; Young Adult
PubMed: 35806102
DOI: 10.3390/ijms23137097