RESUMEN
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.
Asunto(s)
Sarcoma de Células Claras , Neoplasias de los Tejidos Blandos , Carcinogénesis/genética , Cromatina/genética , Humanos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Oncogenes , Proteína EWS de Unión a ARN/genética , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patología , Neoplasias de los Tejidos Blandos/genéticaRESUMEN
Background: Benign soft-tissue tumors of the hand are more common than both their benign bone and malignant soft-tissue counterparts. This study evaluates the characteristics and treatment of benign soft tissue tumors in light of 1 institution's experience. Methods: Histologically confirmed benign soft-tissue tumors of the hand were retrospectively identified using International Classification of Disease codes from 1992 to 2015. A medical chart review was conducted to collect patient demographics, tumor epidemiology, and treatment. Results: A total of 199 soft-tissue tumors were identified. The median patient age at time of treatment was 47.4 ± 14.7 years in age. The majority of tumors were located in the digits (n = 168, 84%) and treated by excision (n = 191, 96%). Localized type tenosynovial giant cell tumors (n = 71, 36%) were the most common and had the highest rates of recurrence (8.5%) in this series. Other frequent histologies included hemangioma, schwannoma, and glomus tumors. Conclusion: Awareness and understanding of tumor characteristics may help physicians with diagnosis and treatment. There is an extensive variety of tumors, but the principles of clinical and imaging diagnosis are common to all of them. Marginal excision for the treatment pain, improvement of function, and cosmetic correction applies to all these tumors independent of the histology.
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Tumor de Células Gigantes de las Vainas Tendinosas , Neoplasias de los Tejidos Blandos , Tumor de Células Gigantes de las Vainas Tendinosas/diagnóstico , Tumor de Células Gigantes de las Vainas Tendinosas/epidemiología , Tumor de Células Gigantes de las Vainas Tendinosas/cirugía , Mano/patología , Mano/cirugía , Humanos , Estudios Retrospectivos , Neoplasias de los Tejidos Blandos/epidemiología , Neoplasias de los Tejidos Blandos/cirugíaRESUMEN
Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.
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Carcinogénesis/genética , Terapia Molecular Dirigida , Proteínas de Fusión Oncogénica/genética , Sarcoma Sinovial/tratamiento farmacológico , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/genética , Histona Desacetilasas/uso terapéutico , Humanos , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Oncogenes/genética , RNA-Seq , Sarcoma Sinovial/genética , Sarcoma Sinovial/patología , Análisis de la Célula IndividualRESUMEN
There is a lack of well validated prognostic biomarkers in osteosarcoma, a rare, recalcitrant disease for which treatment standards have not changed in over 20 years. We performed microRNA sequencing in 74 frozen osteosarcoma biopsy samples, constituting the largest single center translationally analyzed osteosarcoma cohort to date, and we separately analyzed a multi-omic dataset from a large NCI supported national cooperative group cohort. We validated the prognostic value of candidate microRNA signatures and contextualized them in relevant transcriptomic and epigenomic networks. Our results reveal the existence of molecularly defined phenotypes associated with outcome independent of clinicopathologic features. Through machine learning based integrative pharmacogenomic analysis, the microRNA biomarkers identify novel therapeutics for stratified application in osteosarcoma. The previously unrecognized osteosarcoma subtypes with distinct clinical courses and response to therapy could be translatable for discerning patients appropriate for more intensified, less intensified, or alternate therapeutic regimens.
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Neoplasias Óseas/patología , Redes Reguladoras de Genes , MicroARNs/genética , Osteosarcoma/patología , Análisis de Secuencia de ARN/métodos , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Biopsia , Neoplasias Óseas/genética , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Osteosarcoma/genética , Fenotipo , Pronóstico , ARN Mensajero/genética , Análisis de Supervivencia , Adulto JovenRESUMEN
Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth.
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Proteína MioD/metabolismo , Factor 5 Regulador Miogénico/metabolismo , Rabdomiosarcoma/fisiopatología , Transcripción Genética , Animales , Animales Modificados Genéticamente , Inmunoprecipitación de Cromatina , Humanos , Análisis de Secuencia de ADN , Pez CebraRESUMEN
BACKGROUND: Desmoid tumors are rare and exhibit a highly unpredictable natural history. We sought to analyze prognostic factors associated with recurrence in a large single-institution study of patients with desmoid tumors. METHODS: We performed a retrospective review of 177 patients with desmoid tumor who underwent macroscopically complete surgical resection, with or without the addition of radiotherapy (RT) or systemic therapy, from 1970 to 2009. We examined patterns of presentation, all known risk factors for recurrence, and their association with recurrence-free survival (RFS). RESULTS: Twenty-two patients (12 %) had intra-abdominal desmoid tumors, and 155 (88 %) had extra-abdominal tumors. Patterns of presentation included primary (n = 133, 75 %) and locally recurrent (n = 44, 25 %) disease. Treatment was surgery alone in 125 patients (71 %), surgery and RT in 36 (20 %), and surgery and systemic therapy with or without RT in 20 (11 %). Median follow-up was 40 months. Overall, the local relapse rate was 29 %, and 10-year RFS was 60 %. R0 resection status was the only predictor of freedom from local recurrence on multivariate analysis (odds ratio 0.32; 95 % confidence interval 0.15-0.66; P = 0.002). The selective use of adjuvant RT appeared to improve local control in patients with positive margins. CONCLUSIONS: For patients with desmoid tumors undergoing surgery, wide excision with negative margins should be the goal, but not at the expense of function, as fewer than half of patients with positive margins will experience recurrence.
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Fibromatosis Abdominal/mortalidad , Fibromatosis Agresiva/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Complicaciones Posoperatorias , Adulto , Terapia Combinada , Femenino , Fibromatosis Abdominal/patología , Fibromatosis Abdominal/terapia , Fibromatosis Agresiva/patología , Fibromatosis Agresiva/terapia , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: The use of ultrastructural analysis in the diagnostic work-up of histologic specimens has been well studied but less is known about the utility of electron microscopy (EM) in cytopathology. DESIGN: 149,006 non-gynecologic cytology cases at the Massachusetts General Hospital between the years 1993 and 2006 were searched to identify those in which material had been submitted for EM. Cytologic and EM diagnoses were correlated with available histologic diagnoses. The results were put into one of three categories: confirmatory, diagnostic, or insufficient material for diagnosis (IMFD). RESULTS: Material for EM was obtained from 178 cytology cases that included 131 fine-needle aspirates (FNA) and 47 exfoliative specimens. EM provided additional diagnostic information beyond that offered by cytologic examination alone in 32% of cases, and in 48% of cases EM confirmed the cytologic findings. Insufficient material and discrepant results were noted for EM evaluation in 19% of cases and in 1% cases respectively. EM was most useful when applied to FNAs for subclassifying tumors as epithelial or mesenchymal (45.6%), for the diagnosis of non-neoplastic processes (15.7%) such as alveolar proteinosis and amyloidosis, and for the identification of microorganisms (12.2%). In our study, although EM was infrequently applied to exfoliative specimens to distinguish mesothelioma from adenocarcinoma, it proved to be very useful in this setting. CONCLUSION: When adequate material is obtained, EM can contribute significantly to the evaluation of both FNA and exfoliative cytology cases, including the diagnosis and subclassification of epithelial and mesenchymal tumors, non-neoplastic processes, and the identification of microorganisms.
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Microscopía Electrónica de Transmisión/estadística & datos numéricos , Patología Quirúrgica/métodos , Biopsia con Aguja Fina , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Sarcoma developing in association with a metallic orthopaedic prosthesis or hardware is an uncommon, but well recognized complication. We review 12 cases of sarcomas arising in bone or soft tissue at the site of orthopaedic hardware or a prosthetic joint. Nine patients were male, and three were female. Their ages ranged from 18 to 85 (mean 55) years at the time of diagnosis of the malignancy. Five patients had undergone hip arthroplasty for degenerative joint disease, four had been treated with intramedullary nail placement for fracture, two had staples placed for fixation of osteotomy, and one had hardware placed for fracture fixation followed years later by a hip arthroplasty. The time interval between the placement of hardware and diagnosis of sarcoma was known in 11 cases and ranged from 2.5 to 33 (mean 11) years. The patients presented with pain, swelling, or loosening of hardware and were found to have a destructive bone or soft tissue mass on radiography. Two sarcomas were located primarily in the soft tissue and 10 in bone. Seven patients developed osteosarcoma, four malignant fibrous histiocytoma, and one a malignant peripheral nerve sheath tumor. All sarcomas were high grade. Three patients had metastatic disease at the time of diagnosis. Follow-up was available on eight patients: five patients died of disease 2 months to 8 years (mean 26 months) after diagnosis; two patients died without evidence of disease 7 and 30 months after diagnosis; and one patient is alive and free of disease 8 years after diagnosis. Sarcomas that occur adjacent to orthopaedic prostheses or hardware are of varied types, but are usually osteosarcoma or malignant fibrous histiocytoma. They behave aggressively and frequently metastasize. Clinically, they should be distinguished from non-neoplastic reactions associated with implants, such as infection and a reaction to prosthetic wear debris.