Assuntos
Ciclina D1 , Neoplasias Renais , Sarcoma de Células Claras , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Sarcoma de Células Claras/metabolismo , Masculino , Neoplasias Renais/genética , Neoplasias Renais/patologia , Feminino , Criança , Pré-Escolar , Lactente , Prognóstico , Taxa de Sobrevida , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Recidiva Local de Neoplasia , Imuno-Histoquímica , Estadiamento de Neoplasias , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Fusão Oncogênica/genética , Ciclina BRESUMO
OBJECTIVE: To review tumors identified as "clear cell sarcoma" in order to determine similarities to the rare EWS fusion positive jaw and salivary gland tumors clear cell odontogenic carcinoma (CCOC) and clear cell carcinoma of the salivary gland (CCC). METHODS: PubMed was used to collect all reports of clear cell sarcoma (CCS). Search parameters were "clear cell sarcoma" and "CCS." References in the publications were screened and cross-referenced. Data extracted included demographic characteristics, presenting signs and symptoms, radiographic findings, histological and immunohistochemical features and known molecular/genetic aberrations. RESULTS: Clear cell sarcoma has several similarities to CCOC and CCC. All three tumor types have similar histologic appearances including the presence of clear cells, as well as similar genetic profiles in that all harbor an EWSR1-CREB family fusions. Additionally, these tumors appear in soft tissue as well as bone, and can have a prolonged clinical course. CCS can appear anywhere in the body, including the head and neck region. All three tumors appear to have a predilection to women, although CCS may have a slight younger age of onset as compared to CCOC and CCC (3rd vs 5th decade of life, respectively). CONCLUSION: Gaining a better understanding of the similarities and differences between these three tumors may lead to a better understanding of each one.
Assuntos
Carcinoma , Tumores Odontogênicos , Neoplasias das Glândulas Salivares , Sarcoma de Células Claras , Humanos , Feminino , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/metabolismo , Sarcoma de Células Claras/patologia , Proteína EWS de Ligação a RNA/genética , Tumores Odontogênicos/patologia , Neoplasias das Glândulas Salivares/genética , Proteínas de Fusão Oncogênica/genéticaRESUMO
We recently described novel dermal tumors with melanocytic differentiation and morphologic and biological similarities to cutaneous clear cell sarcoma, including CRTC1::TRIM11 cutaneous tumor, and clear cell tumors with melanocytic differentiation and either ACTIN::MITF or MITF::CREM. Here, we describe a series of 3 patients presenting with tumors reminiscent of CRTC1::TRIM11 cutaneous tumor, found to demonstrate a novel MED15::ATF1 fusion. All 3 patients were children (5-16 years old). Primary excision of case 1 showed a circumscribed wedge-shaped silhouette with peripheral intercalation into collagen fibers and scattered lymphoid aggregates. All 3 tumors abutted the epidermis; one showed a junctional component. Tumors were highly cellular and comprised of monomorphic, oval-to-round epithelioid cells arranged in vague nests and short fascicles in variably fibrotic stroma. Mitotic rate was high (hotspot 6-12/mm2), without atypical mitoses. Necrosis was focally present in case 3. All cases showed strong, diffuse nuclear staining for SOX10 and MITF (2/2) but showed variable expression for S100 protein (1/3) and other melanocytic markers-Melan-A (focal in 2/3), HMB45 (focal in 1/3), and Pan-Melanoma (patchy in 1/1). Whole-exome RNA sequencing demonstrated a MED15::ATF1 fusion without any other notable alterations. Cases 1 and 2 were completely excised without recurrence (12 months). Case 3 developed a grossly apparent regional lymph node spread shortly after primary biopsy. The patient was treated with wide excision, radiation, cervical lymph node dissection (4/46 with >75% lymph node replacement), and neoadjuvant and adjuvant nivolumab (alive without disease at cycle 11). This series is presented to aid in future diagnosis of this novel dermal tumor with melanocytic differentiation and emphasize the potential for aggressive biologic behavior, which should be considered in patient management planning.
Assuntos
Melanoma , Sarcoma de Células Claras , Neoplasias Cutâneas , Adolescente , Criança , Pré-Escolar , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Complexo Mediador , Melanoma/diagnóstico , Sarcoma de Células Claras/diagnóstico , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
Clear cell sarcoma (CCS) is a rare but aggressive malignancy that typically occurs in young adults and is characterized by soft tissue tumors of the extremities. CCS can be difficult to distinguish from metastatic melanoma based solely on histology and immunohistochemistry (IHC) because of the significant overlap between them. However, it is imperative to get an accurate clinical diagnosis, as it informs disease staging and treatment options for patient care. Present in approximately 75% of CCS cases, the EWSR1 gene rearrangement detected by fluorescence in situ hybridization (FISH) can help with establishing a diagnosis; the underlying reciprocal translocation has never been reported in cutaneous melanoma. We reviewed a case of a young woman who presented with a confusing picture of widespread lymphadenopathy, cutaneous metastases, and electrolyte derangements and was subsequently diagnosed with metastatic CCS.This case suggests possible value in performing molecular testing when a clinical picture does not correspond with what is expected for melanoma. It also raises the question of whether CCS cases may be underreported. This case highlights an uncommon presentation that may not be recognized as a manifestation of CCS by an oncologist who is not a sarcoma specialist. It is unclear how COVID-19 vaccination contributed to her clinical presentation, and it is also unclear whether an early diagnosis would have changed her clinical outcome.
Assuntos
Melanoma , Sarcoma de Células Claras , Neoplasias Cutâneas , Neoplasias de Tecidos Moles , Feminino , Adulto Jovem , Humanos , Sarcoma de Células Claras/diagnóstico , Sarcoma de Células Claras/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Vacinas contra COVID-19 , Hibridização in Situ FluorescenteRESUMO
Cutaneous tumors with melanocytic differentiation represent a broad group of neoplasms of both melanocytic and non-melanocytic origin. Besides traditional members such as clear-cell sarcoma (CCS) and PEComa, the latter group has recently expanded to also include MITF::CREM fusion-associated tumors, but the available data are limited. Herein, we present a third case of this rare neoplasm which occurred in the temporal region in a 1-year-old girl. It was an infiltratively growing polypoid dermal-based lesion lacking an intraepidermal component. It consisted of cellular solid sheets or small nests of epithelioid to spindled cells with a predominantly eosinophilic and much less commonly clear cytoplasm. The nuclei had round to ovoid shape and exhibited moderate to high-grade atypia and prominent nucleoli. The mitotic activity was 11 mitoses per 10 high-power fields, and atypical mitotic figures were present. Immunohistochemically, the tumor was strongly positive with S100 protein, SOX10, and MITF, while HMB45, tyrosinase, and Melan A were negative. Extensive molecular analysis revealed only MITF::CREM gene fusion. There had no evidence of disease 9 months after the diagnosis. These tumors need to be distinguished from malignant tumors with melanocytic differentiation, primarily from melanoma. However, additional cases still need to be studied to precisely define their biological potential and establish their nosologic status.
Assuntos
Melanoma , Sarcoma de Células Claras , Neoplasias Cutâneas , Feminino , Humanos , Lactente , Neoplasias Cutâneas/patologia , Melanoma/diagnóstico , Melanócitos/patologia , Sarcoma de Células Claras/genética , Diferenciação Celular , Biomarcadores Tumorais/análise , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Modulador de Elemento de Resposta do AMP Cíclico/metabolismoRESUMO
Clear cell sarcoma (CCS) is a rare melanocytic soft tissue sarcoma with a high propensity for lymphatic metastasis and poor prognosis. It is characterized by the translocation of t (12;22), resulting in the rearrangement of the EWSR1 gene and overexpression of MET. Despite improvements in the diagnosis and treatment of soft tissue sarcomas, the management of CCSs remains challenging owing to their rarity, unique biological behaviour and limited understanding of their molecular pathogenesis. The standard treatment for localized CCSs is surgical excision with negative margins. However, there is an ongoing debate regarding the role of adjuvant chemotherapy, radiotherapy and lymphadenectomy in the management of this disease. CCSs are usually resistant to conventional chemotherapy. Targeted therapies, such as sunitinib and MET inhibitors, may provide promising results. Immunotherapy, particularly immune checkpoint inhibitors, is currently under investigation as a potential treatment option for CCSs. Further research is needed to better understand the biology of CCSs and develop effective therapeutic strategies. The purpose of this review is to provide a comprehensive overview of current knowledge and advances in the diagnosis and treatment of CCSs.
Assuntos
Sarcoma de Células Claras , Neoplasias de Tecidos Moles , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/terapia , Sarcoma de Células Claras/patologia , Translocação Genética , Metástase Linfática , Excisão de Linfonodo , Neoplasias de Tecidos Moles/patologiaRESUMO
In addition to melanoma, a large and diverse family of tumors shows melanocytic differentiation. The best characterized member of this family is clear cell sarcoma, which is characterized by EWSR1::ATF1 and EWSR1::CREB1 fusions. These fusions drive the transcription of MITF, the master regulator of melanocytic differentiation. Clear cell tumor with melanocytic differentiation and MITF::CREM translocation is a recently described tumor with some similarities to clear cell sarcoma. However, only a single case has been reported. Here, we describe a second molecularly proven case that arose on the scalp of a newborn baby. In contrast to the prior reported case, the current case showed predominantly high-grade cytomorphologic features with only focal clear cell areas. Similar to the prior case, the tumor showed immunohistochemical evidence of neural crest origin/differentiation with prominent melanocytic differentiation. The fusion breakpoints were also similar and preserved the transcriptional activation domain of CREM, suggesting that CREM hyperactivity is a major feature of this tumor type. The current tumor showed a short-interval recurrence. These results expand the clinical and pathologic spectrum of this potentially new entity.
Assuntos
Melanoma , Sarcoma de Células Claras , Recém-Nascido , Humanos , Sarcoma de Células Claras/genética , Translocação Genética , Diferenciação Celular , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição Associado à Microftalmia , Modulador de Elemento de Resposta do AMP Cíclico/genéticaRESUMO
BACKGROUND: Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults. METHODS: To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines. RESULTS: Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability. CONCLUSION: These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.
Assuntos
Sarcoma de Células Claras , Criança , Adolescente , Adulto Jovem , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/metabolismo , Sarcoma de Células Claras/patologia , Transcriptoma , Genômica , Sequência de Bases , RNA , Proteínas de Fusão Oncogênica/genéticaRESUMO
Malignant gastrointestinal neuroectodermal tumors (MGNETs), also known as "gastrointestinal clear cell sarcoma-like tumors", are very rare, aggressive sarcomas characterized by enteric location, distinctive pathologic features, and EWSR1/FUS::ATF1/CREB1 fusions. Despite identical genetics, the clinicopathologic features of MGNET are otherwise quite different from those of clear cell sarcoma of soft parts. Only exceptional extraenteric MGNET (E-MGNET) has been reported. We report a series of 11 E-MGNETs, the largest to date. Cases diagnosed with MGNET and occurring in nonintestinal locations were retrieved. A clinical follow-up was obtained. The tumors occurred in 3 men and 8 women (range, 14-70 years of age; median, 33 years) and involved the soft tissues of the neck (3), shoulder (1), buttock (2), orbit (1), tongue/parapharyngeal space (1), urinary bladder (1), and falciform ligament/liver (1). Tumors showed morphologic features of enteric MGNET (small, relatively uniform, round to ovoid cells with round, regular nuclei containing small nucleoli growing in multinodular and vaguely lobular patterns, with solid, pseudoalveolar, and pseudopapillary architecture). Immunohistochemical results were S100 protein (11/11), SOX10 (11/11), synaptophysin (3/10), CD56 (7/9), CD117 (3/9), DOG1 (0/4), ALK (4/8), chromogranin A (0/10), HMB-45 (0/11), Melan-A (0/11), tyrosinase (0/4), and MiTF (0/11). Next-generation sequencing results were EWSR1::ATF1 (7 cases), EWSR1::CREB1 (3 cases), and EWSR1::PBX1 (1 case). The EWSR1::PBX1-positive tumor was similar to other cases, including osteoclast-like giant cells, and negative for myoepithelial markers. A clinical follow-up (range, 10-70 months; median, 34 months) showed 4 patients dead of disease (10.5, 12, 25, and 64 months after diagnosis), 1 patient alive with extensive metastases (43 months after diagnosis), 1 patient alive with persistent local disease (11 months after diagnosis), and 4 alive without disease (10, 47, 53, and 70 months after diagnosis). One case is too recent for the follow-up. The clinicopathologic and molecular genetic features of rare E-MGNET are essentially identical to those occurring in intestinal locations. Otherwise, typical E-MGNET may harbor EWSR1::PBX1, a finding previously unreported in this tumor type. As in enteric locations, the behavior of E-MGNET is aggressive, with metastases and/or death from disease in at least 50% of patients. E-MGNET should be distinguished from clear cell sarcoma of soft parts and other tumors with similar fusions. ALK expression appears to be a common feature of tumors harboring EWSR1/FUS::ATF1/CREB1 fusion but is unlikely to predict the therapeutic response to ALK inhibition. Future advances in our understanding of these unusual tumors will hopefully lead to improved nomenclature.
Assuntos
Neoplasias Gastrointestinais , Tumores Neuroectodérmicos , Sarcoma de Células Claras , Masculino , Humanos , Feminino , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Hibridização in Situ Fluorescente , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Proteína EWS de Ligação a RNA/genética , Tumores Neuroectodérmicos/genética , Tumores Neuroectodérmicos/química , Tumores Neuroectodérmicos/patologia , Biologia Molecular , Receptores Proteína Tirosina Quinases/genética , Biomarcadores Tumorais/genética , Proteínas de Fusão Oncogênica/genéticaRESUMO
Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms' tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases.
Assuntos
Neoplasias Renais , Sarcoma de Células Claras , Tumor de Wilms , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Células HEK293 , Proteínas Repressoras/genética , Neoplasias Renais/patologia , Rim/metabolismoRESUMO
BACKGROUND: Clear cell sarcomas (CCSs) are translocated aggressive malignancies, most commonly affecting young adults with a high incidence of metastases and a poor prognosis. Research into the disease is more feasible when adequate models are available. By establishing CCS cell lines from a primary and metastatic lesion and isolating healthy fibroblasts from the same patient, the in vivo process is accurately reflected and aspects of clinical multistep carcinogenesis recapitulated. METHODS: Isolated tumor cells and normal healthy skin fibroblasts from the same patient were compared in terms of growth behavior and morphological characteristics using light and electron microscopy. Tumorigenicity potential was determined by soft agar colony formation assay and in vivo xenograft applications. While genetic differences between the two lineages were examined by copy number alternation profiles, nuclear magnetic resonance spectroscopy determined arginine methylation as epigenetic features. Potential anti-tumor effects of a protein arginine N-methyltransferase type I (PRMT1) inhibitor were elicited in 2D and 3D cell culture experiments using cell viability and apoptosis assays. Statistical significance was calculated by one-way ANOVA and unpaired t-test. RESULTS: The two established CCS cell lines named MUG Lucifer prim and MUG Lucifer met showed differences in morphology, genetic and epigenetic data, reflecting the respective original tissue. The detailed cell line characterization especially in regards to the epigenetic domain allows investigation of new innovative therapies. Based on the epigenetic data, a PRMT1 inhibitor was used to demonstrate the targeted antitumor effect; normal tissue cells isolated and immortalized from the same patient were not affected with the IC50 used. CONCLUSIONS: MUG Lucifer prim, MUG Lucifer met and isolated and immortalized fibroblasts from the same patient represent an ideal in vitro model to explore the biology of CCS. Based on this cell culture model, novel therapies could be tested in the form of PRMT1 inhibitors, which drive tumor cells into apoptosis, but show no effect on fibroblasts, further supporting their potential as promising treatment options in the combat against CCS. The data substantiate the importance of tailored therapies in the advanced metastatic stage of CCS.
Assuntos
Sarcoma de Células Claras , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/metabolismo , Sarcoma de Células Claras/patologia , Linhagem Celular , Inibidores Enzimáticos , Arginina/genética , Arginina/metabolismo , Arginina/uso terapêutico , Epigênese Genética , Linhagem Celular Tumoral , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/uso terapêutico , Proteínas Repressoras/genéticaRESUMO
BACKGROUND: Among pediatric renal tumors, rhabdoid tumor of the kidney (RTK) and clear cell sarcoma of the kidney (CCSK) are rare and associated with an unfavorable prognosis, while congenital mesoblastic nephroma (CMN) is associated with a good prognosis. Methylation of the Ras association domain-containing protein 1 isoform A (RASSF1A) promoter has been reported to correlate with a poor prognosis in patients with Wilms tumors, while its methylation status is unclear in other types of pediatric renal tumors. METHOD: DNA methylation of the RASSF1A promoter in several pediatric renal tumors was analyzed with pyrosequencing. In order to clarify the correlation between expression of RASSF1A and DNA methylation of its promoter, the RTK cell line was treated with 5-Aza-2'-deoxycytidine (5-Aza-dC). RASSF1A was overexpressed in the RTK cell line to evaluate its functional effects. RESULTS: Quantitative methylation analysis demonstrated hypermethylation in the RASSF1A promoter region in RTK and CCSK, but not CMN. The 5-Aza-dC treatment induced demethylation of the RASSF1A promoter as well as increased RASSF1A mRNA expression. The transduction of RASSF1A has an effect on the suppression of viability and proliferation of RTK cells. CONCLUSION: DNA methylation-mediated deficiency of RASSF1A might be involved in the development and aggressiveness of some pediatric renal tumors and correlated with a poor prognosis.
Assuntos
Neoplasias Renais , Nefroma Mesoblástico , Tumor Rabdoide , Sarcoma de Células Claras , Humanos , Criança , Metilação de DNA , Proteínas Supressoras de Tumor/genética , Tumor Rabdoide/genética , Sarcoma de Células Claras/genética , Neoplasias Renais/patologia , Rim/patologia , Azacitidina/farmacologia , Nefroma Mesoblástico/genética , Decitabina , Linhagem Celular TumoralRESUMO
Pediatric renal tumors are a rare entity and majority of these tumors are accounted for by Wilms tumor. The second most common renal tumor is clear cell sarcoma of the kidney (CSSK). Most of the CSSK have either BCOR-internal tandem duplication (ITD) or YWHAE-NUTM2B/E fusion. The sarcomas with BCOR-CCNB3 fusion are well documented in soft tissue and bone tumors, but are extremely rare in the pediatric renal setting. We are reporting an extremely rare case of pediatric clear cell sarcoma of the kidney (CSSK) with BCOR-CCNB3 fusion, which was a diagnostic challenge on morphological grounds. A final diagnosis could only be reached after multiple reviews and NGS based RNA fusion testing. We have also performed a brief review of literature which revealed eight (8) other cases of this rare entity.
Assuntos
Neoplasias Renais , Sarcoma de Células Claras , Humanos , Criança , Sarcoma de Células Claras/diagnóstico , Sarcoma de Células Claras/genética , Proteínas Repressoras/genética , Fatores de Transcrição , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Biomarcadores Tumorais/genética , Rim/patologia , Ciclina B , Proteínas Proto-Oncogênicas/genéticaRESUMO
Clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal malignancy, characterized by BCOR internal tandem duplication (ITD), YWHAE rearrangement, BCOR-CCNB3 fusion, and lack of other consistent structural alteration. We accidentally identified TP53 deletion in CCSK, which was often associated with adverse clinical outcomes. In this study, we assessed the incidence as well as the clinical relevance of these molecules in CCSK patients. BCOR ITD, YWHAE rearrangement, BCOR-CCNB3 fusion and TP53 status were examined by polymerase chain reaction, fluorescence in situ hybridization, or Sanger sequencing in a cohort of 39 patients with CCSK. Among them, 34 cases (87.18%) had BCOR ITD, 1 (2.56%) had YWHAE rearrangement, and 1 (2.56%) had BCOR-CCNB3 gene fusion. The remaining 3 (7.69%) harbored none of these aberrations. BCOR ITD, YWHAE rearrangement and BCOR-CCNB3 were mutually exclusive. Furthermore, 25.64% of the cohort acquired TP53 aberration (10/39, 3 with both copy number deletion and point mutation, 6 with deletion only, and 1 with mutation only), all of which were associated with BCOR ITD. Patients with or without BCOR ITD or TP53 aberration did not differ in demographic characteristics such as sex, onset age, or tumor stage at diagnosis. However, the overall survival rates and progression-free survival rates of BCOR ITD or TP53 deletion groups showed obvious downward trends, albeit not all reaching statistical significance. Patients with both BCOR ITD and TP53 deletion had the poorest prognosis.
Assuntos
Neoplasias Renais , Sarcoma de Células Claras , Humanos , Criança , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Hibridização in Situ Fluorescente , Relevância Clínica , Proteínas Repressoras/genética , Proteínas Repressoras/análise , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Proteína Supressora de Tumor p53/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/análiseRESUMO
Transcription dysregulation is common in sarcomas driven by oncogenic transcription factors. Clear cell sarcoma of soft tissue (CCSST) is a rare sarcoma with poor prognosis presently with no therapy. It is characterized by a balanced t(12;22) (q13;q12) chromosomal translocation, resulting in a fusion of the Ewing's sarcoma gene EWSR1 with activating transcription factor 1 (ATF1) to give an oncogene EWSR1-ATF1. Unlike normal ATF1, whose transcription activity is dependent on phosphorylation, EWSR1-ATF1 is constitutively active to drive ATF1-dependent gene transcription to cause tumorigenesis. No EWSR1-ATF1-targeted therapies have been identified due to the challenges in targeting intracellular transcription factors. Through proteomics screening to identify potential druggable targets for CCSST, we discovered protein arginine methyltransferase 5 (PRMT5) as a novel protein to interact with EWSR1-ATF1. PRMT5 is a type II protein arginine methyltransferase to symmetrically dimethylate arginine residues in substrate proteins to regulate a diverse range of activities including gene transcription, RNA splicing, and DNA repair. We found that PRMT5 enhances EWSR1-ATF1-mediated gene transcription to sustain CCSST cell proliferation. Genetic silencing of PRMT5 in CCSST cells resulted in severely impaired cell proliferation and EWSR1-ATF1-driven transcription. Furthermore, we demonstrate that the clinical-stage PRMT5 inhibitor JNJ-64619178 potently and efficaciously inhibited CCSST cell growth in vitro and in vivo. These results provide new insights into PRMT5 as a transcription regulator and warrant JNJ-64619178 for further clinical development to treat CCSST patients.
Assuntos
Fator 1 Ativador da Transcrição , Proteínas de Fusão Oncogênica , Proteína-Arginina N-Metiltransferases , Proteína EWS de Ligação a RNA , Sarcoma de Células Claras , Neoplasias de Tecidos Moles , Humanos , Fator 1 Ativador da Transcrição/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/metabolismo , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismo , Transcrição Gênica , Regulação Neoplásica da Expressão GênicaRESUMO
ABSTRACT: Also referred to as "osteoclast-rich, clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT)," malignant gastrointestinal neuroectodermal tumor is a newly described, rare, aggressive sarcoma that commonly arises in the small bowel, stomach, and colon. Histogenesis is likely from an autonomous nervous system-related primitive cell of neural crest origin. The hallmark genetic finding of EWS-CREB1 or EWS-ATF1 fusion transcripts clinches the diagnosis. Annular constrictive lesions tend to be smaller, show homogenous contrast enhancement on computed tomography, and may present with bowel obstruction. Larger, expansile masses tend to be exophytic and show heterogeneous contrast enhancement. Surgical resection is the mainstay of treatment. Frequent recurrences, metastases, and death from disease in 75% of patients portend a poor prognosis. Targeted chemotherapy based on specific tumor pathways is being developed.
Assuntos
Neoplasias Gastrointestinais , Tumores Neuroectodérmicos , Sarcoma de Células Claras , Neoplasias de Tecidos Moles , Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/patologia , Humanos , Tumores Neuroectodérmicos/diagnóstico por imagem , Tumores Neuroectodérmicos/patologia , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologiaRESUMO
The resistance to transcription factor-mediated reprogramming into pluripotent stem cells is one of the distinctive features of cancer cells. Here we dissect the profiles of reprogramming factor binding and the subsequent transcriptional response in cancer cells to reveal its underlying mechanisms. Using clear cell sarcomas (CCSs), we show that the driver oncogene EWS/ATF1 misdirects the reprogramming factors to cancer-specific enhancers and thereby impairs the transcriptional response toward pluripotency that is otherwise provoked. Sensitization to the reprogramming cue is observed in other cancer types when the corresponding oncogenic signals are pharmacologically inhibited. Exploiting this oncogene dependence of the transcriptional "stiffness," we identify mTOR signaling pathways downstream of EWS/ATF1 and discover that inhibiting mTOR activity substantially attenuates the propagation of CCS cells in vitro and in vivo. Our results demonstrate that the early transcriptional response to cell fate perturbations can be a faithful readout to identify effective therapeutics targets in cancer cells.
Assuntos
Oncogenes , Sarcoma de Células Claras , Humanos , Sarcoma de Células Claras/genética , Transdução de Sinais , Serina-Treonina Quinases TOR , Fatores de Transcrição/genéticaRESUMO
Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.