Gene Summary

Gene:SMARCA4; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
Aliases: BRG1, CSS4, SNF2, SWI2, MRD16, RTPS2, BAF190, SNF2L4, SNF2LB, hSNF2b, BAF190A
Summary:The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription activator BRG1
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Medulloblastoma
  • WNK Lysine-Deficient Protein Kinase 1
  • Ovarian Cancer
  • Whole Genome Sequencing
  • Translocation
  • Ultraviolet Rays
  • Zinc Finger E-box-Binding Homeobox 1
  • Chromosomal Proteins, Non-Histone
  • Wilms Tumour
  • Vascular Endothelial Growth Factor C
  • Immunohistochemistry
  • Transcription
  • Chromosome 19
  • Transfection
  • Rhabdoid Tumours
  • Virus Replication
  • Wnt Signaling Pathway
  • Zinc Fingers
  • DNA Helicases
  • Xenograft Models
  • Transforming Growth Factor beta2
  • Transcriptional Activation
  • TNF
  • Two-Dimensional Difference Gel Electrophoresis
  • Chromatin Assembly and Disassembly
  • Retinoic Acid
  • Tumor Suppressor Proteins
  • Cervical Cancer
  • Biomarkers, Tumor
  • Lung Cancer
  • Triple Negative Breast Cancer
  • DNA-Binding Proteins
  • p53 Protein
  • Tumor Burden
  • Nuclear Proteins
  • Young Adult
  • Bladder Cancer
  • X-linked Nuclear Protein
  • Cancer Gene Expression Regulation
  • p300-CBP Transcription Factors
  • Mutation
  • rac1 GTP-Binding Protein
  • p21-Activated Kinases
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SMARCA4 (cancer-related)

Farnaby W, Koegl M, Roy MJ, et al.
BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.
Nat Chem Biol. 2019; 15(7):672-680 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

Xue Y, Meehan B, Macdonald E, et al.
CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary.
Nat Commun. 2019; 10(1):558 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16

Xue Y, Meehan B, Fu Z, et al.
SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer.
Nat Commun. 2019; 10(1):557 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.

Cuevas D, Valls J, Gatius S, et al.
Targeted sequencing with a customized panel to assess histological typing in endometrial carcinoma.
Virchows Arch. 2019; 474(5):585-598 [PubMed] Related Publications
The two most frequent types of endometrial cancer (EC) are endometrioid (EEC) and serous carcinomas (SC). Differential diagnosis between them is not always easy. A subset of endometrial cancers shows misleading microscopical features, which cause problems in differential diagnosis, and may be a good scenario for next-generation sequencing. Previous studies have assessed the usefulness of targeted sequencing with panels of generic cancer-associated genes in EC histological typing. Based on the analysis of TCGA (The Cancer Genome Atlas), EEC and SC have different mutational profiles. In this proof of principle study, we have performed targeted sequencing analysis with a customized panel, based on the TCGA mutational profile of EEC and SC, in a series of 24 tumors (16 EEC and 8 SC). Our panel comprised coding and non-coding sequences of the following genes: ABCC9, ARID1A, ARID5B, ATR, BCOR, CCND1, CDH19, CHD4, COL11A1, CSDE1, CSMD3, CTCF, CTNNB1, EP300, ERBB2, FBXW7, FGFR2, FOXA2, KLLN, KMT2B, KRAS, MAP3K4, MKI67, NRAS, PGAP3, PIK3CA, PIK3R1, PPP2R1A, PRPF18, PTEN, RPL22, SCARNA11, SIN3A, SMARCA4, SPOP, TAF1, TP53, TSPYL2, USP36, and WRAP53. Targeted sequencing validation by Sanger sequencing and immunohistochemistry was performed in a group of genes. POLE mutation status was assessed by Sanger sequencing. The most mutated genes were PTEN (93.7%), ARID1A (68.7%), PIK3CA (50%), and KMT2B (43.7%) for EEC, and TP53 (87.5%), PIK3CA (50%), and PPP2R1A (25%) for SC. Our panel allowed correct classification of all tumors in the two categories (EEC, SC). Coexistence of mutations in PTEN, ARID1A, and KMT2B was diagnostic of EEC. On the other hand, absence of PTEN, ARID1A, and KMT2B mutations in the presence of TP53 mutation was diagnostic of SC. This proof of concept study demonstrates the suitability of targeted sequencing with a customized endometrial cancer gene panel as an additional tool for confirming histological typing.

Ye C, Wang J, Li W, et al.
Effective treatment of advanced alveolar soft part sarcoma with sunitinib: A case report.
Medicine (Baltimore). 2018; 97(51):e13584 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
RATIONALE: Alveolar soft part sarcoma (ASPS) is a very rare soft tissue sarcoma. ASPS often occurs in deep soft tissues of the lower extremities, and develops into metastatic diseases. Chemotherapy is considered to be ineffective in patients with ASPS, which constitutes a very important clinical challenge. The strategy for ASPS treatment still requires clarification in order to improve survival outcome. Patients concerns: A 19-year-old female patient presented with a 5-year history of painless lump in the left knee and 4-day cough. Her previous medical history was unremarkable. Menstruation and family history were also normal in this patient, whose physical examination and laboratory test results showed no abnormalities.
DIAGNOSIS: ASPS was confirmed by clinical manifestations, radiological data and pathological diagnosis of the biopsy of left knee.
INTERVENTIONS AND OUTCOMES: This patient received circulating tumor DNA detection and only a mutation of the SMARCA4 gene was detected. The patient received sunitinib treatment (37.5 mg once daily) for 15 months and showed partial regression of lung metastatic lesions and stabilization of brain metastases. She achieved 15 months of progression free survival.
CONCLUSIONS: Sunitinib is effective for the treatment of advanced ASPS with lung and brain metastases. The current patient had long-term progression free survival under sunitinib administration.

Meisenberg C, Pinder SI, Hopkins SR, et al.
Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability.
Mol Cell. 2019; 73(2):212-223.e7 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Cohesin subunits are frequently mutated in cancer, but how they function as tumor suppressors is unknown. Cohesin mediates sister chromatid cohesion, but this is not always perturbed in cancer cells. Here, we identify a previously unknown role for cohesin. We find that cohesin is required to repress transcription at DNA double-strand breaks (DSBs). Notably, cohesin represses transcription at DSBs throughout interphase, indicating that this is distinct from its known role in mediating DNA repair through sister chromatid cohesion. We identified a cancer-associated SA2 mutation that supports sister chromatid cohesion but is unable to repress transcription at DSBs. We further show that failure to repress transcription at DSBs leads to large-scale genome rearrangements. Cancer samples lacking SA2 display mutational patterns consistent with loss of this pathway. These findings uncover a new function for cohesin that provides insights into its frequent loss in cancer.

Rago F, DiMare MT, Elliott G, et al.
Degron mediated BRM/SMARCA2 depletion uncovers novel combination partners for treatment of BRG1/SMARCA4-mutant cancers.
Biochem Biophys Res Commun. 2019; 508(1):109-116 [PubMed] Related Publications
Recent studies have highlighted that cancer cells with a loss of the SWI/SNF complex catalytic subunit BRG1 are dependent on the remaining ATPase, BRM, making it an attractive target for cancer therapy. However, an understanding of the extent of target inhibition required to arrest cell growth, necessary to develop an appropriate therapeutic strategy, remains unknown. Here, we utilize tunable depletion of endogenous BRM using the SMASh degron, and interestingly observe that BRG1-mutant lung cancer cells require near complete depletion of BRM to robustly inhibit growth both in vitro and in vivo. Therefore, to identify pathways that synergize with partial BRM depletion and afford a deeper response, we performed a genome-wide CRISPR screen and discovered a combinatorial effect between BRM depletion and the knockout of various genes of the oxidative phosphorylation pathway and the anti-apoptotic gene MCL1. Together these studies provide an important framework to elucidate the requirements of BRM inhibition in the BRG1-mutant state with implications on the feasibility of targeting BRM alone, as well as reveal novel insights into pathways that can be exploited in combination toward deeper anti-tumor responses.

Tegeder I, Thiel K, Erkek S, et al.
Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors.
J Neurooncol. 2019; 141(1):43-55 [PubMed] Related Publications
PURPOSE: Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency.
METHODS: The functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using a Drosophila melanogaster model of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells.
RESULTS: Knockdown of Snr1, the fly orthologue of SMARCB1, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g. CG10348, the fly orthologue of transcriptional regulator PRDM16. Subsequently, PRDM16 was found to be over-expressed in ATRT samples and knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells reduced proliferation.
CONCLUSIONS: These results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT.

Anderson WJ, Hornick JL
Immunohistochemical correlates of recurrent genetic alterations in sarcomas.
Genes Chromosomes Cancer. 2019; 58(2):111-123 [PubMed] Related Publications
Accurate diagnosis of sarcomas relies on the integration of clinical, histopathological and molecular features. Our understanding of the latter has increased dramatically in recent years with the application of high-throughput sequencing. Concomitantly, the role of immunohistochemistry has expanded as genomic alterations have been exploited by the development of diagnostic markers that serve as surrogates for their detection. Herein, we review selected immunohistochemical markers that can infer the presence of diverse molecular events. These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan-TRK); amplifications in well-differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4). Protein correlates of single nucleotide variants (beta-catenin in desmoid fibromatosis) and epigenetic alterations (histone H3K27me3 in malignant peripheral nerve sheath tumor) and markers discovered through gene expression profiling (NKX2.2 and MUC4) are also discussed.

Williams EA, Miller JJ, Tummala SS, et al.
TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations.
Acta Neuropathol Commun. 2018; 6(1):106 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM). Here, we characterized the subset of IDH-wt GBMs that do not have TERTp mutations. In a cohort of 121 adult grade IV gliomas, we identified 109 IDH-wt GBMs, after excluding 11 IDH-mutant cases and one H3F3A -mutant case. Within the IDH-wt cases, 16 cases (14.7%) were TERTp wild-type (TERTp-wt). None of the 16 had BRAF V600E or H3F3A G34 hotspot mutations. When compared to TERTp mutants, patients with TERTp-wt GBMs, were significantly younger at first diagnosis (53.2 years vs. 60.7 years, p = 0.0096), and were more frequently found to have cerebellar location (p = 0.0027). Notably, 9 of 16 (56%) of TERTp-wt GBMs contained a PIK3CA or PIK3R1 mutation, while only 16/93 (17%) of TERTp-mutant GBMs harbored these alterations (p = 0.0018). As expected, 8/16 (50%) of TERTp-wt GBMs harbored mutations in the BAF complex gene family (ATRX, SMARCA4, SMARCB1, and ARID1A), compared with only 8/93 (9%) of TERTp-mutant GBMs (p = 0.0003). Mutations in BAF complex and PI3K pathway genes co-occurred more frequently in TERTp-wt GBMs (p = 0.0002), an association that has been observed in other cancers, suggesting a functional interaction indicative of a distinct pathway of gliomagenesis. Overall, our finding highlights heterogeneity within WHO-defined IDH wild-type GBMs and enrichment of the TERTp-wt subset for BAF/PI3K-altered tumors, potentially comprising a distinct clinical subtype of gliomas.

Wu S, Fatkhutdinov N, Fukumoto T, et al.
SWI/SNF catalytic subunits' switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells.
Nat Commun. 2018; 9(1):4116 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Inactivation of the subunits of SWI/SNF complex such as ARID1A is synthetically lethal with inhibition of EZH2 activity. However, mechanisms of de novo resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated cells. SMARCA4 loss upregulates anti-apoptotic genes in the EZH2 inhibitor-resistant cells. EZH2 inhibitor-resistant ARID1A-mutated cells are hypersensitive to BCL2 inhibitors such as ABT263. ABT263 is sufficient to overcome resistance to an EZH2 inhibitor. In addition, ABT263 synergizes with an EZH2 inhibitor in vivo in ARID1A-inactivated ovarian tumor mouse models. Together, these data establish that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 underlies the acquired resistance to EZH2 inhibitors. They suggest BCL2 inhibition alone or in combination with EZH2 inhibition represents urgently needed therapeutic strategy for ARID1A-mutated cancers.

S AS, Goutham R N A, Mohan S S
In silico screening of cancer-associated mutations in the HSA domain of BRG1 and its role in affecting the Arp-HSA sub-complex of SWI/SNF.
Comput Biol Chem. 2018; 77:109-115 [PubMed] Related Publications
SWI/SNF (SWItch/Sucrose Non-Fermentable) complexes regulate the gene expression programs by remodeling the nucleosome architecture of the chromatin functional elements. These large multi-component complexes comprise eight or more subunits and are conserved from yeast to human. Noticeably, nuclear actin and actin-related proteins (Arps) are an integral part of these complexes and are known to directly interact with the helicase-SANT-associated (HSA) domain of ATPase subunit. Recently, SWI/SNF subunits are gaining importance because of the prevalence of cancer-causing mutations associated with them. The functional characterization of the mutations in the SWI/SNF subunits is important for understanding their role in tumorigenesis and identifying potential therapeutic strategies. To study the actin-related complex of human SWI/SNF and the cancer-associated mutations interfering Arp assembly with the ATPase subunit, we modelled the structure of the β-actin-BAF53A-HSA complex based on the yeast Arp-HSA complex (PDB ID: 4I6M). Seven deleterious mutations in the HSA domain of BRG1 were identified based on the functional screening of cancer-associated mutations in the COSMIC database. Detailed structural analysis of the six mutations (R466H, R469W, Y489C, K502N, R513Q and R521P) based on molecular dynamics (MD) simulations reveal the distinct effect of each mutation in destabilizing the structure of the Arp-HSA complex. Predominantly we could notice the long-range effect of the HSA mutations in influencing the dynamics of the Arp subunits.

Jin ML, Kim YW, Jeong KW
BAF53A regulates androgen receptor-mediated gene expression and proliferation in LNCaP cells.
Biochem Biophys Res Commun. 2018; 505(2):618-623 [PubMed] Related Publications
The actin-like protein of the SWI/SNF complex, BAF53A, regulates gene expression by the gene-specific chromatin remodeling of target genes. However, the function of BAF53A in the androgen receptor pathway in prostate cancer cells remains unclear. Here, we demonstrated that BAF53A positively regulates the expression of endogenous AR target genes (e.g. PSA, TMPRSS2, FKBP5, and KLK2) in LNCaP cells. It functions as a coactivator in AR-mediated transcription by interacting with other nuclear receptor coactivators, such as p300 and FLII, and is associated with AR in the presence of dihydrotestosterone (DHT). The DHT-induced recruitment of BAF53A to the proximal and distal androgen response elements (AREs) of the PSA gene in the presence of BRG1 (but not BRM) was inhibited by an AR antagonist, suggesting the coactivator function of BAF53A in the SWI/SNF complex. Depletion of BAF53A in LNCaP cells resulted in a significant decrease in growth rate. Furthermore, the expression of BAF53A in prostate cancer tissue was significantly elevated, compared to that in normal prostate tissue, and correlated with the expression of AR, and BRG1, but not BRM. Therefore, our results suggested that BAF53A plays an important role in the expression of AR target genes in prostate cancer, and can be used clinically for the treatment of prostate cancer.

Hung YP, Sholl LM
Diagnostic and Predictive Immunohistochemistry for Non-Small Cell Lung Carcinomas.
Adv Anat Pathol. 2018; 25(6):374-386 [PubMed] Related Publications
Non-small cell lung carcinoma (NSCLC) accounts for significant morbidity and mortality worldwide, with most patients diagnosed at advanced stages and managed increasingly with targeted therapies and immunotherapy. In this review, we discuss diagnostic and predictive immunohistochemical markers in NSCLC, one of the most common tumors encountered in surgical pathology. We highlight 2 emerging diagnostic markers: nuclear protein in testis (NUT) for NUT carcinoma; SMARCA4 for SMARCA4-deficient thoracic tumors. Given their highly aggressive behavior, proper recognition facilitates optimal management. For patients with advanced NSCLCs, we discuss the utility and limitations of immunohistochemistry (IHC) for the "must-test" predictive biomarkers: anaplastic lymphoma kinase, ROS1, programmed cell death protein 1, and epidermal growth factor receptor. IHC using mutant-specific BRAF V600E, RET, pan-TRK, and LKB1 antibodies can be orthogonal tools for screening or confirmation of molecular events. ERBB2 and MET alterations include both activating mutations and gene amplifications, detection of which relies on molecular methods with a minimal role for IHC in NSCLC. IHC sits at the intersection of an integrated surgical pathology and molecular diagnostic practice, serves as a powerful functional surrogate for molecular testing, and is an indispensable tool of precision medicine in the care of lung cancer patients.

Huang LY, Zhao J, Chen H, et al.
Nat Commun. 2018; 9(1):3569 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multi-component SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription. However, the upstream signaling pathways regulating Brg1 protein stability and its physiological contribution to carcinogenesis remain largely elusive. Here we report that Brg1 is a bona fide ubiquitin substrate of SCF

Abbaszadegan MR, Taghehchian N, Li L, et al.
Contribution of KCTD12 to esophageal squamous cell carcinoma.
BMC Cancer. 2018; 18(1):853 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
BACKGROUND: It has been shown that the expression of potassium channel tetramerization domain containing 12 (KCTD12) as a regulator of GABAB receptor signaling is reversely associated with gastrointestinal stromal tumors. In present study we examined the probable role of KCTD12 in regulation of several signaling pathways and chromatin remodelers in esophageal squamous cell carcinoma (ESCC).
METHODS: KCTD12 ectopic expression was done in KYSE30 cell line. Comparative quantitative real time PCR was used to assess the expression of stem cell factors and several factors belonging to the WNT/NOTCH and chromatin remodeling in transfected cells in comparison with non-transfected cells.
RESULTS: We observed that the KCTD12 significantly down regulated expression of NANOG, SOX2, SALL4, KLF4, MAML1, PYGO2, BMI1, BRG1, MSI1, MEIS1, EGFR, DIDO1, ABCC4, ABCG2, and CRIPTO1 in transfected cells in comparison with non-transfected cells. Migration assay showed a significant decrease in cell movement in ectopic expressed cells in comparison with non-transfected cells (p = 0.02). Moreover, KCTD12 significantly decreased the 5FU resistance in transfected cells (p = 0.01).
CONCLUSIONS: KCTD12 may exert its inhibitory role in ESCC through the suppression of WNT /NOTCH, stem cell factors, and chromatin remodelers and can be introduced as an efficient therapeutic marker.

Lee HH, Kim SY, Jung ES, et al.
Mutation heterogeneity between primary gastric cancers and their matched lymph node metastases.
Gastric Cancer. 2019; 22(2):323-334 [PubMed] Related Publications
BACKGROUND: The acquisition of an invasive phenotype by a tumor cell is a crucial step of malignant transformation. The underlying genetic mechanisms in gastric cancer (GC) are not well understood.
METHODS: We performed whole-exome sequencing of 15 pairs of primary GC and their matched lymph node (LN) metastases (10 primary GCs with single matched LNs and 5 primary GCs with three LNs per case, respectively). Somatic alterations including single nucleotide variations, short insertions/deletions including locus-level microsatellite instability and copy number alterations were identified and compared between the primary and metastatic LN genomes.
RESULTS: Mutation abundance was comparable between the primary GC and LN metastases, but the extent of mutation overlap or the mutation heterogeneity between primary and LN genomes varied substantially. Primary- or LN-specific mutations could be distinguished from common mutations in terms of mutation spectra and functional categories, suggesting that the mutation forces are not constant during gastric carcinogenesis. A spatial distribution revealed TP53 mutations as common mutations along with a number of region-specific mutations, such as primary-specific SMARCA4 and LN-specific CTNNB1 mutations. The subclonal architectures of common mutations were largely conserved between primary GC and LN metastatic genomes. The mutation-based phylogenetic analyses further showed that LN metastases may have arisen from homogeneous subclones of primary tumors.
CONCLUSIONS: The abundance and spatial distribution of mutations may provide clues on the evolutionary relationship between primary and matched LN genomes. Gene-level analyses further distinguished the early addicted cancer drivers such as TP53 mutations from late acquired region-specific mutations.

Tessema M, Rossi MR, Picchi MA, et al.
Common cancer-driver mutations and their association with abnormally methylated genes in lung adenocarcinoma from never-smokers.
Lung Cancer. 2018; 123:99-106 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
OBJECTIVES: Lung adenocarcinoma in never-smokers accounts for 15-20% of all lung cancer. Although targetable mutations are more prevalent in these tumors, the biological and clinical importance of coexisting and/or mutually exclusive abnormalities is just emerging. This study evaluates the relationships between common genetic and epigenetic aberrations in these tumors.
MATERIALS AND METHODS: Next-generation sequencing was employed to screen 20 commonly mutated cancer-driver genes in 112 lung adenocarcinomas from never-smokers. The relationship of these mutations with cancer-related methylation of 59 genes, and geographical/ethnic differences in the prevalence for mutations compared to multiple East Asian never-smoker lung adenocarcinoma cohorts was studied.
RESULTS: The most common driver mutation detected in 40% (45/112) of the tumors was EGFR, followed by TP53 (18%), SETD2 (11%), and SMARCA4 (11%). Over 72% (81/112) of the cases have mutation of at least one driver gene. While 30% (34/112) of the tumors have co-mutations of two or more genes, 42% (47/112) have only one driver gene mutation. Differences in the prevalence for some of these mutations were seen between adenocarcinomas in East Asian versus US (mainly Caucasian) never-smokers including a significantly lower rate of EGFR mutation among the US patients. Interestingly, aberrant methylation of multiple cancer-related genes was significantly associated with EGFR wildtype tumors. Among 15 differentially methylated genes by EGFR mutation, 14 were more commonly methylated in EGFR wildtype compared to mutant tumors. These findings were independently validated using publicly available data.
CONCLUSION: Most lung adenocarcinomas from never-smokers harbor targetable mutation/co-mutations. In the absence of EGFR mutation that drives 40% of these tumors, EGFR wildtype tumors appear to develop by acquiring aberrant promoter methylation that silences tumor-suppressor genes.

Albani A, Perez-Rivas LG, Reincke M, Theodoropoulou M
Endocr Pract. 2018; 24(10):907-914 [PubMed] Related Publications
OBJECTIVE: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically.
METHODS: Literature review.
RESULTS: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 ( USP8) gene in almost half of Cushing disease tumors.
CONCLUSION: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease.
ABBREVIATIONS: ACTH = adrenocorticotropic hormone; BRG1 = Brahma-related gene 1; CABLES1 = CDK5 and ABL1 enzyme substrate 1; CD = Cushing disease; CNC = Carney complex; DICER1 = cytoplasmic endoribonuclease III; EGFR = epidermal growth factor receptor; GR = glucocorticoid receptor; IL = interleukin; MEN = multiple endocrine neoplasia; miRNA = microRNA; POMC = proopiomelanocortin; SSTR = somatostatin receptor; USP8 = ubiquitin-specific protease 8.

Fukumoto T, Magno E, Zhang R
SWI/SNF Complexes in Ovarian Cancer: Mechanistic Insights and Therapeutic Implications.
Mol Cancer Res. 2018; 16(12):1819-1825 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Ovarian cancer remains the most lethal gynecologic malignancy in the developed world. Despite the unprecedented progress in understanding the genetics of ovarian cancer, cures remain elusive due to a lack of insight into the mechanisms that can be targeted to develop new therapies. SWI/SNF chromatin remodeling complexes are genetically altered in approximately 20% of all human cancers. SWI/SNF alterations vary in different histologic subtypes of ovarian cancer, with

Caumanns JJ, Wisman GBA, Berns K, et al.
ARID1A mutant ovarian clear cell carcinoma: A clear target for synthetic lethal strategies.
Biochim Biophys Acta Rev Cancer. 2018; 1870(2):176-184 [PubMed] Related Publications
SWI/SNF chromatin remodeling complexes play an important role in the epigenetic regulation of chromatin structure and gene transcription. Mutual exclusive subunits in the SWI/SNF complex include the DNA targeting members ARID1A and ARID1B as well as the ATPases SMARCA2 and SMARCA4. SWI/SNF complexes are mutated across many cancer types. The highest mutation incidence is found in ARID1A, primarily consisting of deleterious mutations. Current advances have reported synthetic lethal interactions with the loss of ARID1A in several cancer types. In this review, we discuss targets that are only important for tumor growth in an ARID1A mutant context. We focus on synthetic lethal strategies with ARID1A loss in ovarian clear cell carcinoma, a cancer with the highest ARID1A mutation incidence (46-57%). ARID1A directed lethal strategies that can be exploited clinically include targeting of the DNA repair proteins PARP and ATR, and the epigenetic factors EZH2, HDAC2, HDAC6 and BRD2.

Choi JR, Koh SB, Kim HR, et al.
Radon Exposure-induced Genetic Variations in Lung Cancers among Never Smokers.
J Korean Med Sci. 2018; 33(29):e207 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Background: Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking. After smoking, radon exposure is the second leading cause and the primary risk factor of lung cancer among never smokers. Exposure to radon can lead to genetic and epigenetic alterations in tumor genomes affecting genes and pathways involved in lung cancer development. The present study sought to explore genetic alterations associated with LCINS exposed to radon gas indoors.
Methods: Genetic associations were assessed via a case-control study of LCINS (39 cases and 30 controls) using next generation sequencing. Associations between genetic mutations and high exposure to radon were investigated by OncoPrint and heatmap graphs. Bioinformatic analysis was conducted using various tools. According radon exposure levels, we divided subjects in two groups of cases and controls.
Results: We found that ABL2 rs117218074, SMARCA4 rs2288845, PIK3R2 rs142933317, MAPK1 rs1803545, and androgen receptor (AR) rs66766400 were associated with LCINS exposed to high radon levels. Among these, Chromodomain helicase DNA-binding protein 4 (CHD4) rs74790047, TSC2 rs2121870, and AR rs66766408 were identified as common exonic mutations in both lung cancer patients and normal individuals exposed to high levels of radon indoor.
Conclusion: We identified that CHD4 rs74790047, TSC2 rs2121870, and AR rs66766408 are found to be common exonic mutations in both lung cancer patients and normal individuals exposed to radon indoors. Further analysis is needed to determine whether these genes are completely responsible for LCINS exposed to residential radon.

Esposito MR, Binatti A, Pantile M, et al.
Somatic mutations in specific and connected subpathways are associated with short neuroblastoma patients' survival and indicate proteins targetable at onset of disease.
Int J Cancer. 2018; 143(10):2525-2536 [PubMed] Related Publications
Neuroblastoma (NB) is an embryonic malignancy of the sympathetic nervous system with heterogeneous biological, morphological, genetic and clinical characteristics. Although genomic studies revealed the specific biological features of NB pathogenesis useful for new therapeutic approaches, the improvement of high-risk (HR)-NB patients overall survival remains unsatisfactory. To further clarify the biological basis of disease aggressiveness, we used whole-exome sequencing to examine the genomic landscape of HR-NB patients at stage M with short survival (SS) and long survival (LS). Only a few genes, including SMARCA4, SMO, ZNF44 and CHD2, were recurrently and specifically mutated in the SS group, confirming the low recurrence of common mutations in this tumor. A systems biology approach revealed that in the two patient groups, mutations occurred in different pathways. Mutated genes (ARHGEF11, CACNA1G, FGF4, PTPRA, PTK2, ANK3, SMO, NTNG2, VCL and NID2) regulate the MAPK pathway associated with the organization of the extracellular matrix, cell motility through PTK2 signaling and matrix metalloproteinase activity. Moreover, we detected mutations in LAMA2, PTK2, LAMA4, and MMP14 genes, impairing MET signaling, in SFI1 and CHD2 involved in centrosome maturation and chromosome remodeling, in AK7 and SPTLC2, which regulate the metabolism of nucleotides and lipoproteins, and in NALCN, SLC12A1, SLC9A9, which are involved in the transport of small molecules. Notably, connected networks of somatically mutated genes specific for SS patients were identified. The detection of mutated genes present at the onset of disease may help to address an early treatment of HR-NB patients using FDA-approved compounds targeting the deregulated pathways.

Pulikkan JA, Hegde M, Ahmad HM, et al.
CBFβ-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia.
Cell. 2018; 174(1):172-186.e21 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The fusion oncoprotein CBFβ-SMMHC, expressed in leukemia cases with chromosome 16 inversion, drives leukemia development and maintenance by altering the activity of the transcription factor RUNX1. Here, we demonstrate that CBFβ-SMMHC maintains cell viability by neutralizing RUNX1-mediated repression of MYC expression. Upon pharmacologic inhibition of the CBFβ-SMMHC/RUNX1 interaction, RUNX1 shows increased binding at three MYC distal enhancers, where it represses MYC expression by mediating the replacement of the SWI/SNF complex component BRG1 with the polycomb-repressive complex component RING1B, leading to apoptosis. Combining the CBFβ-SMMHC inhibitor with the BET inhibitor JQ1 eliminates inv(16) leukemia in human cells and a mouse model. Enhancer-interaction analysis indicated that the three enhancers are physically connected with the MYC promoter, and genome-editing analysis demonstrated that they are functionally implicated in deregulation of MYC expression. This study reveals a mechanism whereby CBFβ-SMMHC drives leukemia maintenance and suggests that inhibitors targeting chromatin activity may prove effective in inv(16) leukemia therapy.

Lissanu Deribe Y, Sun Y, Terranova C, et al.
Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer.
Nat Med. 2018; 24(7):1047-1057 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.

Haase S, Garcia-Fabiani MB, Carney S, et al.
Mutant ATRX: uncovering a new therapeutic target for glioma.
Expert Opin Ther Targets. 2018; 22(7):599-613 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
INTRODUCTION: ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered: We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives. Expert opinion: ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g. DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

Katoh M
Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review).
Int J Mol Med. 2018; 42(2):713-725 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
β‑catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E‑cadherin/CDH1, N‑cadherin/CDH2, VE‑cadherin/CDH5 and α‑catenins), transmembrane‑type mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gain‑of‑function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss‑of‑function CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative β‑catenin target genes. β‑catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. β‑catenin and NF‑κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. β‑catenin‑targeted therapeutics are functionally classified into β‑catenin inhibitors targeting upstream regulators (AZ1366, ETC‑159, G007‑LK, GNF6231, ipafricept, NVP‑TNKS656, rosmantuzumab, vantictumab, WNT‑C59, WNT974 and XAV939), β‑catenin inhibitors targeting protein‑protein interactions (CGP049090, CWP232228, E7386, ICG‑001, LF3 and PRI‑724), β‑catenin inhibitors targeting epigenetic regulators (PKF118‑310), β‑catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and β‑catenin inhibitors targeting transmembrane‑type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first‑line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, β‑catenin inhibitors may be applicable for the prevention of organ fibrosis, second‑line HCC prevention and treating β‑catenin‑driven cancer. The multi‑layered prevention and treatment strategy of β‑catenin‑related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.

Gillis NE, Taber TH, Bolf EL, et al.
Thyroid Hormone Receptor β Suppression of RUNX2 Is Mediated by Brahma-Related Gene 1-Dependent Chromatin Remodeling.
Endocrinology. 2018; 159(6):2484-2494 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Thyroid hormone receptor β (TRβ) suppresses tumor growth through regulation of gene expression, yet the associated TRβ-mediated changes in chromatin assembly are not known. The chromatin ATPase brahma-related gene 1 (BRG1; SMARCA4), a key component of chromatin-remodeling complexes, is altered in many cancers, but its role in thyroid tumorigenesis and TRβ-mediated gene expression is unknown. We previously identified the oncogene runt-related transcription factor 2 (RUNX2) as a repressive target of TRβ. Here, we report differential expression of BRG1 in nonmalignant and malignant thyroid cells concordant with TRβ. BRG1 and TRβ have similar nuclear distribution patterns and significant colocalization. BRG1 interacts with TRβ, and together, they are part of the regulatory complex at the RUNX2 promoter. Loss of BRG1 increases RUNX2 levels, whereas reintroduction of TRβ and BRG1 synergistically decreases RUNX2 expression. RUNX2 promoter accessibility corresponded to RUNX2 expression levels. Inhibition of BRG1 activity increased accessibility of the RUNX2 promoter and corresponding expression. Our results reveal a mechanism of TRβ repression of oncogenic gene expression: TRβ recruitment of BRG1 induces chromatin compaction and diminishes RUNX2 expression. Therefore, BRG1-mediated chromatin remodeling may be obligatory for TRβ transcriptional repression and tumor suppressor function in thyroid tumorigenesis.

Agaimy A, Amin MB, Gill AJ, et al.
SWI/SNF protein expression status in fumarate hydratase-deficient renal cell carcinoma: immunohistochemical analysis of 32 tumors from 28 patients.
Hum Pathol. 2018; 77:139-146 [PubMed] Related Publications
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive RCC type, originally described in the setting of hereditary leiomyomatosis and RCC syndrome, which is defined by germline FH gene inactivation. Inactivation of components of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex is involved in renal medullary carcinoma (SMARCB1/INI1 loss), clear cell RCC (PBRM1 loss), and subsets of dedifferentiated RCC of clear cell, chromophobe, and papillary types (loss of different SWI/SNF components). FH-RCC and SWI/SNF-deficient RCC share anaplastic nuclear features and highly aggressive course. We analyzed 32 FH-RCCs from 28 patients using 7 commercially available SWI/SNF antibodies (SMARCB1/INI1, SMARCA2, SMARCA4, SMARCC1, SMARCC2, PBRM1, and ARID1A). Variable loss of SMARCB1, ARID1A, and SMARCC1 was observed in 1 of 31, 2 of 31, and 1 of 29 evaluable cases, respectively; 3 of these 4 SWI/SNF-deficient tumors had confirmed FH mutations. No correlation of SWI/SNF loss with solid or sarcomatoid features was observed. Two tumors with SMARCB1 and ARID1A deficiency had available SWI/SNF molecular data; both lacked SMARCB1 and ARID1A mutations. The remaining 5 SWI/SNF components were intact in all cases. Especially PBRM1 seems not to be involved in the pathogenesis or progression of FH-RCC. Our data showed that a subset of FH-RCC (12%) have a variable loss of SWI/SNF complex subunits, likely as secondary genetic events. This should not be confused with SWI/SNF-deficient RCC of other types. Evaluation of FH and SWI/SNF together with comprehensive molecular genetic profiling is needed to explore possible prognostic implications of FH/SWI-SNF double deficiency and to better understand the somatic mutation landscape in high-grade RCC.

Machado I, Yoshida A, Morales MGN, et al.
Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, "undifferentiated small round cell tumors". A clinicopathologic, immunophenotypic and molecular analysis.
Ann Diagn Pathol. 2018; 34:1-12 [PubMed] Related Publications
BACKGROUND: Despite extensive immunohistochemical (IHC) and molecular studies combined with morphologic findings, a group of round/ovoid cell tumors histologically similar to Ewing sarcomas (ES) but lacking EWSR1-rearrangements may remain unclassifiable.
DESIGN: We retrospectively analyzed 41 Ewing-like tumors (formalin-fixed, paraffin-embedded) previously determined as negative or non-informative for EWSR1-rearrangements by FISH and/or RT-PCR. A new histopathology revision and additional IHC and molecular analyses were carried out in order to investigate whether additional IHC and/or molecular testing in combination with the morphological findings may help in reaching a definitive diagnosis.
RESULTS: Almost all the tumors (n=40) involved soft tissue and/or bone and half the patients died of disease. In the archival cases all diagnoses were Ewing sarcoma (ES), Ewing-like sarcoma (ELS), myoepithelial tumor and undifferentiated sarcoma (US). In the new review all the tumors were re-classified as, ES (n=16), Ewing-like tumor with EWSR1 rearrangement and amplification and possible EWSR1-NFATC2 gene fusion (n=1), CIC-rearranged sarcomas or undifferentiated sarcoma, most consistent with CIC-rearranged sarcoma (n=7), sarcoma with BCOR-alteration or undifferentiated sarcoma, consistent with BCOR-associated sarcoma (n=3), neuroblastoma (n=2), unclassifiable neoplasm with neuroblastic differentiation (n=1), malignant rhabdoid tumor (n=2), lymphoblastic lymphoma (n=1), clear cell sarcoma of the gastrointestinal tract (n=1), small cell carcinoma (n=1), sclerosing rhabdomyosarcoma (n=1), desmoplastic small round cell tumor (n=1), malignant peripheral sheath nerve tumor (n=1), poorly-differentiated synovial sarcoma (n=1), Possible gastrointestinal stromal tumor/GIST with predominant round cells (n=1) and possible SMARCA4-deficient-sarcoma (n=1). NKX2.2, ETV4 and BCOR immunoreactivity was observed in all ES, CIC-rearranged sarcomas and sarcomas with BCOR alteration, respectively. CIC-rearrangement by FISH was observed in many of the CIC-rearranged sarcomas.
CONCLUSION: Our analysis of 41 Ewing-like tumors confirms that there may be a significant pathological and IHC overlap among Ewing-like tumors, with prognostic and therapeutic impacts. Additional IHC (NKX2.2, ETV4 and BCOR) and molecular studies including FUS, CIC or BCOR analysis may support the final diagnosis when FISH or RT-PCR fail to detect EWSR1-rearrangements. Any molecular findings should always be interpreted in relation to the specific clinical and pathological context.

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