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1.
Zhen Ci Yan Jiu ; 46(2): 95-9, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33788428

RESUMO

OBJECTIVE: To observe the effect of moxibustion on the growth of tumor and expression of fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial cell growth factor receptor 2 (VEGFR2) in mice with sarcoma, so as to explore its mechanisms underlying inhibiting sarcoma growth. METHODS: C57BL/6J mice (half male and half female) were inoculated with S180 sarcoma cells to form transplanted tumors, and divided into model control, medication and moxibustion groups, with 10 mice in each group. Moxibustion was applied to the transplanted tumor directly for 10 min, once a day for 14 days. After the treatment, Luminex liquid suspension chip was used to detect the contents of serum vascular endothelial growth factor (VEGF), FGFR1 and VEGFR2. The weight of the transplanted tumor was measured, and the expression of VEGF in the transplanted tumor was detected by immunohistochemistry, and the expression of FGFR1 and VEGFR2 mRNAs in the transplanted tumor was detected by fluorescence in situ hybridization. RESULTS: The tumor weight, VEGF immunoactivity, serum VEGF, VEGFR2 and FGFR1 contents, and expression levels of VEGFR2 and FGFR1 mRNAs in the transplanted tumor were significantly lower in the moxibustion group than in the model group (P<0.001, P<0.01, P<0.05). Compared with the model group, the tumor weight was remarkably lower in the medication group (P<0.001). Compared with the medication group, th VEGF immunoactivity and the contents of serum VEGF, VEGFR2 and FGFR1 were significantly lower in the moxibustion group (P<0.01, P<0.05). H.E. staining showed a large number of red blood cells were observed in the microenvironment of the transplanted tumor in the moxibustion group rather than in the medication group. CONCLUSION: Moxibustion can inhibit the growth of tumor in mice with sarcoma, which may be related to its function in reducing the expression of FGFR1 and VEGFR2 to inhibit angiogenesis.


Assuntos
Moxibustão , Sarcoma , Animais , Feminino , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Sarcoma/genética , Sarcoma/terapia , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
2.
Medicine (Baltimore) ; 100(11): e25008, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725976

RESUMO

ABSTRACT: The tumor microenvironment (TME) plays an important role in the occurrence and development of soft tissue sarcoma (STS). A number of studies have shown that to inhibit tumor growth, the TME can be remodeled into an environment unsuitable for tumor proliferation. However, a lack of understanding exists regarding the dynamic regulation of TME.In this study, we used CIBERSORT and ESTIMATE calculation methods from the Cancer Genome Atlas (TCGA) database to calculate the proportion of tumor infiltrating immune cells (TICs) and the number of immune and stromal components in 263 STS samples. Differential expression genes (DEGs) shared by Immune Score and Stromal Score were obtained via difference analysis. Univariate Cox regression analysis and construction of protein-protein interaction (PPI) networks were applied to the DEGs.Through intersection analysis of univariate COX and PPI, PLCG2 was determined as the indicator. Further analysis showed that PLCG2 expression was positively correlated with the survival of STS patients. Gene set enrichment analysis (GSEA) showed that genes in the highly expressed PLCG2 group were enriched in immune-related activities. In the low-expression PLCG2 group, genes were enriched in the E2F, G2M, and MYC pathways. Difference analysis and correlation analysis showed that CD8+ T cells, gamma delta T cells, monocytes, and M1 macrophages were positively correlated with PLCG2 expression, indicating that PLCG2 may represent the immune status of TME.Therefore, the level of PLCG2 may aid in determining the prognosis of STS patients, especially the status of TME. These data provide additional insights into the remodeling of TME.


Assuntos
Fosfolipase C gama/metabolismo , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Microambiente Tumoral/genética , Biomarcadores Tumorais , Bases de Dados Genéticas , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/metabolismo , Ativação de Macrófagos/genética , Masculino , Modelos de Riscos Proporcionais , Mapas de Interação de Proteínas , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Células Estromais/metabolismo , Transcriptoma
3.
Medicine (Baltimore) ; 100(5): e23787, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592836

RESUMO

ABSTRACT: Soft tissue sarcomas (STSs) are heterogeneous at the clinical with a variable tendency of aggressive behavior. In this study, we constructed a specific DNA methylation-based classification to identify the distinct prognosis-subtypes of STSs based on the DNA methylation spectrum from the TCGA database. Eventually, samples were clustered into 4 subgroups, and their survival curves were distinct from each other. Meanwhile, the samples in each subgroup reflected differentially in several clinical features. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was also conducted on the genes of the corresponding promoter regions of the above-described specific methylation sites, revealing that these genes were mainly concentrated in certain cancer-associated biological functions and pathways. In addition, we calculated the differences among clustered methylation sites and performed the specific methylation sites with LASSO algorithm. The selection operator algorithm was employed to derive a risk signature model, and a prognostic signature based on these methylation sites performed well for risk stratification in STSs patients. At last, a nomogram consisted of clinical features and risk score was developed for the survival prediction. This study declares that DNA methylation-based STSs subtype classification is highly relevant for future development of personalized therapy as it identifies the prediction value of patient prognosis.


Assuntos
Metilação de DNA/genética , Nomogramas , Sarcoma/classificação , Neoplasias de Tecidos Moles/classificação , Algoritmos , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Humanos , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Sarcoma/genética , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/mortalidade
4.
Zhonghua Bing Li Xue Za Zhi ; 50(1): 38-43, 2021 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-33396985

RESUMO

Objective: To describe the clinicopathological features of pulmonary artery intimal sarcoma (PAIS), and to understand its molecular alterations. Methods: Sixty cases of pulmonary artery endarterectomy performed at the China-Japan Friendship Hospital, Beijing, China from January 2017 to January 2020 were reviewed. Clinical data of 5 patients with pulmonary artery intimal sarcoma were collected. Hematoxylin-eosin staining, immunohistochemistry staining and fluorescence in situ hybridization (FISH) were performed to evaluate the pathological features. RNA sequencing was conducted to assess the fusion gene changes in PAIS. Results: The detection rate of PAIS was 8.3% (5/60), with the median age of 49 years and a female predominance. Their clinical manifestations were non-specific. Histopathological examination showed that the tumors were composed of malignant spindle or epithelioid cells, with various degrees of atypia. Focal heterologous osteosarcomatous or leiomyosarcomatous differentiation was noted. The tumor cells could express PDGFRA, CDK4 and MDM2 with co-amplification of MDM2, CDK4 and EGFR genes. RNA sequencing detected multiple in-frame fusions in the tumors. Conclusions: PAIS is a rare, highly heterogeneous, and poorly-or un-differentiated sarcoma accompanied by complex changes of multiple genes.It has no known effective treatments, and thus has a poor prognosis.


Assuntos
Sarcoma , Neoplasias Vasculares , Biomarcadores Tumorais , China , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Artéria Pulmonar/cirurgia , Sarcoma/genética , Sarcoma/cirurgia , Neoplasias Vasculares/genética , Neoplasias Vasculares/cirurgia
5.
Nat Commun ; 12(1): 498, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479225

RESUMO

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.


Assuntos
Algoritmos , Neoplasias Ósseas/genética , Metilação de DNA , Aprendizado de Máquina , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Neoplasias Ósseas/classificação , Neoplasias Ósseas/diagnóstico , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Humanos , Internet , Reprodutibilidade dos Testes , Sarcoma/classificação , Sarcoma/diagnóstico , Sensibilidade e Especificidade , Neoplasias de Tecidos Moles/classificação , Neoplasias de Tecidos Moles/diagnóstico
6.
Am J Surg Pathol ; 45(1): 77-92, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32889887

RESUMO

Although diagnosis of high-grade uterine mesenchymal tumors (UMTs) exhibiting classic morphologic features is straightforward, diagnosis is more challenging in tumors in which prototypical features are poorly developed, focal, and/or coexist with features seen in other neoplasms. Here, we sought to define the repertoire of somatic genetic alterations in diagnostically challenging UMTs with myomelanocytic differentiation, including some reported as perivascular epithelioid cell tumors (PEComas). In 17 samples from 15 women, the tumors were histologically heterogenous. Immunohistochemical expression of at least 1 melanocytic marker (HMB45, Melan-A, or MiTF) was identified in all tumors, and of myogenic markers (desmin or smooth muscle actin) in most tumors. Targeted massively parallel sequencing revealed several genetic alterations, most commonly in TP53 (41% mutation, 12% deletion), TSC2 (29% mutation, 6% deletion), RB1 (18% deletion), ATRX (24% mutation), MED12 (12% mutation), BRCA2 (12% deletion), CDKN2A (6% deletion) as well as FGFR3, NTRK1, and ERBB3 amplification (each 6%). Gene rearrangements (JAZF1-SUZ12; DNAJB6-PLAG1; and SFPQ-TFE3) were identified in 3 tumors. Integrating histopathologic, immunohistochemical, and genetic findings, tumors from 4 patients were consistent with malignant PEComa (1 TFE3-rearranged); 6 were classified as leiomyosarcomas; 3 showed overlapping features of PEComa and other sarcoma types (leiomyosarcoma or low-grade endometrial stromal sarcoma); and 2 were classified as sarcoma, not otherwise specified. Our findings suggest that diagnostically challenging UMTs with myomelanocytic differentiation represent a heterogenous group of neoplasms which harbor a diverse repertoire of somatic genetic alterations; these genetic alterations can aid classification.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias de Células Epitelioides Perivasculares/diagnóstico , Sarcoma/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias de Células Epitelioides Perivasculares/classificação , Neoplasias de Células Epitelioides Perivasculares/genética , Sarcoma/classificação , Sarcoma/genética , Neoplasias Uterinas/classificação , Neoplasias Uterinas/genética
7.
Gene ; 764: 145105, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32882333

RESUMO

Sarcoma (SARC) represents a group of highly histological and molecular heterogeneous rare malignant tumors with poor prognosis. There are few proposed classifiers for predicting patient's outcome. The Cancer Proteome Atlas (TPCA) and The Cancer Genome Atlas (TCGA) databases provide multi-omics datasets that enable a comprehensive investigation for this disease. The proteomic expression profile of SARC patients along with the clinical information was downloaded. 55 proteins were found to be associated with overall survival (OS) of patients using univariate Cox regression analysis. We developed a prognostic risk signature that comprises seven proteins (AMPKALPHA, CHK1, S6, ARID1A, RBM15, ACETYLATUBULINLYS40, and MSH6) with robust predictive performance using multivariate Cox stepwise regression analysis. Additionally, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters. Patients in high-risk group also have worse progression free intervals (PFI) than that of patients in low-risk group, but not for disease free intervals (DFI). The signature was validated using transcriptomic profile of SARC patients from TCGA. Potential mechanisms between high- and low-risk groups were identified using differentially expressed genes (DEGs) analysis. These DEGs were primarily enriched in RAS and MPAK signaling pathways. The signature protein molecules are candidate biomarkers for SARC, and the analysis of computational biology in tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinctly immune landscapes of high- and low-risk patients. Together, we constructed a prognostic signature for predicting outcomes for SARC integrating proteomic and transcriptomic profiles, this might have value in guiding clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Testes Genéticos/métodos , Sarcoma/mortalidade , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Mapeamento de Interação de Proteínas , Proteômica , Curva ROC , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/imunologia , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
8.
Nat Commun ; 11(1): 6410, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335088

RESUMO

Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.


Assuntos
Sarcoma/terapia , Análise de Célula Única/métodos , Microambiente Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Transplante de Medula Óssea , Linfócitos T CD8-Positivos/imunologia , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Camundongos Endogâmicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sarcoma/genética , Sarcoma/imunologia , Evasão Tumoral , Microambiente Tumoral/genética , Sequenciamento Completo do Exoma
10.
Lancet Oncol ; 21(11): 1423-1432, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33035459

RESUMO

BACKGROUND: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. METHODS: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing. FINDINGS: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. INTERPRETATION: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941). FUNDING: Epizyme.


Assuntos
Benzamidas/administração & dosagem , Piridonas/administração & dosagem , Proteína SMARCB1/genética , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridonas/efeitos adversos , Piridonas/farmacocinética , Sarcoma/genética , Sarcoma/patologia , Resultado do Tratamento , Adulto Jovem
11.
DNA Cell Biol ; 39(9): 1558-1572, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32845706

RESUMO

Sarcomas are a broad family of cancers that arise from cells of mesenchymal origin in virtually every tissue of the body. Some transcription factors (TFs) have been reported to be involved in the pathogenesis and metastasis of sarcomas. The expression of certain long noncoding RNAs (lncRNAs) has been correlated with the degree of cancer prognosis. There is an urgent need to effectively integrate TFs and lncRNA/microRNA/mRNA regulatory axis and further identify more key regulators that play crucial roles in sarcomas. We performed a network-based computational analysis to investigate the lncRNA-TF cross talks via integrating lncRNA-TF ceRNA interactions and TF-TF protein-protein interactions. Multiple topology analyses were performed to the sarcomas-related global lncRNA-TF network. Several lncRNAs or TFs with central topology structures were identified as key regulators and used to locate a hub-associated lncRNA-TF subnetwork. Three functional modules were identified from the sarcomas-related global lncRNA-TF network, which have shown significant pathway enrichment and prognosis capability. The lncRNAs and TFs of these modules were shown to participate in sarcoma-related biological phenomena through involving in mitogen-activated protein kinases (MAPK), Jak-STAT, and transforming growth factor (TGF-beta) signaling pathways. More importantly, a subset of core lncRNA-TF cross talks that might form positive feedback loops to control biological processes of sarcomas was identified. These core lncRNA-TF positive feedback loops showed more TF binding affinity than other lncRNAs. All the results can help us uncover the molecular mechanism of sarcomas and provide a novel way for diagnosis biomarker and therapeutic target identification.


Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , RNA Longo não Codificante/genética , Sarcoma/genética , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Retroalimentação Fisiológica , Humanos , Sistema de Sinalização das MAP Quinases , RNA Longo não Codificante/metabolismo , Sarcoma/patologia , Fatores de Transcrição/metabolismo
12.
Proc Natl Acad Sci U S A ; 117(34): 20776-20784, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32788348

RESUMO

Transcription factor fusions (TFFs) are present in ∼30% of soft-tissue sarcomas. TFFs are not readily "druggable" in a direct pharmacologic manner and thus have proven difficult to target in the clinic. A prime example is the CIC-DUX4 oncoprotein, which fuses Capicua (CIC) to the double homeobox 4 gene, DUX4. CIC-DUX4 sarcoma is a highly aggressive and lethal subtype of small round cell sarcoma found predominantly in adolescents and young adults. To identify new therapeutic targets in CIC-DUX4 sarcoma, we performed chromatin immunoprecipitation sequencing analysis using patient-derived CIC-DUX4 cells. We uncovered multiple CIC-DUX4 targets that negatively regulate MAPK-ERK signaling. Mechanistically, CIC-DUX4 transcriptionally up-regulates these negative regulators of MAPK to dampen ERK activity, leading to sustained CIC-DUX4 expression. Genetic and pharmacologic MAPK-ERK activation through DUSP6 inhibition leads to CIC-DUX4 degradation and apoptotic induction. Collectively, we reveal a mechanism-based approach to therapeutically degrade the CIC-DUX4 oncoprotein and provide a precision-based strategy to combat this lethal cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Sarcoma/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Fosfatase 6 de Especificidade Dupla/genética , Fosfatase 6 de Especificidade Dupla/metabolismo , Feminino , Genes Homeobox , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Oncogênicas/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética , Sarcoma/genética , Sarcoma de Ewing/genética , Sarcoma de Células Pequenas/genética , Fatores de Transcrição/genética , Translocação Genética/genética
13.
PLoS One ; 15(7): e0236097, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32673360

RESUMO

Soft tissue sarcomas (STS) is a set of rare malignant tumor originated from mesoderm. For the prognosis of sarcoma, early diagnosis is important, however, currently no mature and non-invasive method for diagnosis exists. MicroRNAs (miRNAs) are a class of noncoding RNAs and their expression varies greatly, especially during tumor activity. The purpose of this study was to construct a predictive model for the diagnosis of sarcomas based on the relative expression level of miRNA in serum. miRNA array expression data of 677 samples including 402 malignant sarcoma samples and 275 healthy samples was used to construct the prediction model. Based on 6 gene pairs, random generalized linear model (RGLM) was constructed, with an accuracy of 100% in the internal test dataset and of 74.3% in the merged external dataset in prediction whether a serum sample was obtained from a sarcoma patient, with a specificity of 100% in the internal test dataset and 90.5% in the external dataset. In conclusion, our serum miRNA-pair classifier has the potential to be used for the screening of sarcoma with high accuracy and specificity.


Assuntos
Biologia Computacional , MicroRNAs/sangue , MicroRNAs/genética , Sarcoma/sangue , Sarcoma/diagnóstico , Adulto , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Programas de Rastreamento , Sarcoma/genética
14.
Nat Commun ; 11(1): 2423, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415069

RESUMO

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/metabolismo , Estresse Oxidativo , Sarcoma de Ewing/patologia , Adulto , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Condrócitos/metabolismo , Metilação de DNA , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Hidrazinas/química , Células-Tronco Mesenquimais/metabolismo , Camundongos , Repetições de Microssatélites , Mitocôndrias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Oncogenes , Interferência de RNA , Fatores de Transcrição SOXD/metabolismo , Sarcoma/genética
15.
PLoS Genet ; 16(4): e1008642, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32310940

RESUMO

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been reported in several cases. We performed comprehensive molecular profiling on samples from 14 patients diagnosed with UESL. Congruent with prior reports, we identified structural variants in chr19q13 in 10 of 13 evaluable tumors. From whole transcriptome sequencing, we observed striking expressional activity of the entire C19MC region. Concordantly, in 7 of 7 samples undergoing miRNAseq, we observed hyperexpression of the miRNAs within this cluster to levels >100 fold compared to matched normal tissue or a non-C19MC amplified cancer cell line. Concurrent TP53 mutation or copy number loss was identified in all evaluable tumors with evidence of C19MC overexpression. We find that C19MC miRNAs exhibit significant negative correlation to TP53 regulatory miRNAs and K-Ras regulatory miRNAs. Using RNA-seq we identified that pathways relevant to cellular differentiation as well as mRNA translation machinery are transcriptionally enriched in UESL. In summary, utilizing a combination of next-generation sequencing and high-density arrays we identify the combination of C19MC hyperexpression via chromosomal structural event with TP53 mutation or loss as highly recurrent genomic features of UESL.


Assuntos
Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 19/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/genética , Mutação , Neoplasias Embrionárias de Células Germinativas/genética , Sarcoma/genética , Proteína Supressora de Tumor p53/genética , Aneuploidia , Criança , Pré-Escolar , Feminino , Genes ras/genética , Instabilidade Genômica/genética , Humanos , Lactente , Masculino , Sítio de Iniciação de Transcrição , Proteína Supressora de Tumor p53/deficiência , Regulação para Cima
16.
Cell ; 181(2): 211, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32302562

RESUMO

Tazemetostat is the first epigenetic therapy to gain FDA approval in a solid tumor. This lysine methyltransferase inhibitor targets EZH2, the enzymatic subunit of the PRC2 transcriptional silencing complex. Tumors with mutations in subunits of the SWI/SNF chromatin remodeling complex, inclusive of most epithelioid sarcomas, are sensitive to EZH2 inhibition.


Assuntos
Benzamidas/uso terapêutico , Epigênese Genética/genética , Piridonas/uso terapêutico , Sarcoma/tratamento farmacológico , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Inibidores Enzimáticos/farmacologia , Epigenômica , Terapia Genética/métodos , Humanos , Proteínas Nucleares/metabolismo , Sarcoma/genética , Fatores de Transcrição/metabolismo
17.
Nat Commun ; 11(1): 1723, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265444

RESUMO

Metaplastic breast carcinoma (MBC) is a highly aggressive form of triple-negative cancer (TNBC), defined by the presence of metaplastic components of spindle, squamous, or sarcomatoid histology. The protein profiles underpinning the pathological subtypes and metastatic behavior of MBC are unknown. Using multiplex quantitative tandem mass tag-based proteomics we quantify 5798 proteins in MBC, TNBC, and normal breast from 27 patients. Comparing MBC and TNBC protein profiles we show MBC-specific increases related to epithelial-to-mesenchymal transition and extracellular matrix, and reduced metabolic pathways. MBC subtypes exhibit distinct upregulated profiles, including translation and ribosomal events in spindle, inflammation- and apical junction-related proteins in squamous, and extracellular matrix proteins in sarcomatoid subtypes. Comparison of the proteomes of human spindle MBC with mouse spindle (CCN6 knockout) MBC tumors reveals a shared spindle-specific signature of 17 upregulated proteins involved in translation and 19 downregulated proteins with roles in cell metabolism. These data identify potential subtype specific MBC biomarkers and therapeutic targets.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteoma/metabolismo , Sarcoma/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/genética , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/secundário , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundário , Transição Epitelial-Mesenquimal/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Redes e Vias Metabólicas/genética , Metaplasia/genética , Metaplasia/metabolismo , Camundongos , Pessoa de Meia-Idade , Mutação , Biossíntese de Proteínas/genética , Proteoma/genética , Proteômica , Sarcoma/genética , Sarcoma/secundário , Fuso Acromático/genética , Fuso Acromático/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
18.
World Neurosurg ; 139: 12-19, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32251827

RESUMO

BACKGROUND: Ewing-like sarcoma with capicua transcriptional repressor (CIC) rearrangement is a unique class of undifferentiated round cell sarcomas characterized by CIC-double homeobox 4 gene fusion. Despite showing great histologic resemblance to Ewing sarcomas, they have proved to be a distinct pathological entity from the immunohistochemistry and genetic examinations and the response to treatment. We have presented a case of CIC-rearranged Ewing-like sarcoma with cerebral metastasis managed with operative resection and gamma knife radiosurgery. CASE DESCRIPTION: A 56-year-old woman had initially presented with an ulcerating lesion of the right fifth toe. The histological and immunohistochemical analysis revealed features consistent with CIC-rearranged Ewing-like sarcoma, which was confirmed with genetic analysis. Despite aggressive local control and a multidrug chemotherapy regimen, the patient developed multifocal metastases involving the lungs, femur, and cerebrum. The cerebral lesions were managed with surgery and gamma knife radiosurgery, with mixed results. CONCLUSION: CIC-rearranged Ewing-like sarcomas have recently been recognized as a distinct disease entity with a highly aggressive course. Treatment paradigms have yet to be defined to properly manage such an aggressive pathological process.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Neoplasias Pulmonares/terapia , Metastasectomia , Radiocirurgia , Sarcoma/terapia , Neoplasias de Tecidos Moles/cirurgia , Dedos do Pé/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Feminino , Neoplasias Femorais/diagnóstico por imagem , Neoplasias Femorais/genética , Neoplasias Femorais/secundário , Neoplasias Femorais/terapia , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Proteínas Repressoras/genética , Sarcoma/diagnóstico por imagem , Sarcoma/genética , Sarcoma/secundário , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Cirurgia Torácica Vídeoassistida , Tomografia Computadorizada por Raios X
19.
Int J Mol Sci ; 21(5)2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32155762

RESUMO

Undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors in the pediatric population. Molecular techniques are instrumental for the categorization and differential diagnosis of these tumors. A subgroup of recently identified soft tissue sarcomas with undifferentiated round cell morphology was characterized by Capicua transcriptional receptor (CIC) rearrangements. Recently, an array-based DNA methylation analysis of undifferentiated tumors with small blue round cell histology was shown to provide a highly robust and reproducible approach for precisely classifying this diagnostically challenging group of tumors. We describe the case of an undifferentiated sarcoma of the abdominal wall in a 12-year-old girl. The patient presented with a voluminous mass of the abdominal wall, and multiple micro-nodules in the right lung. The tumor was unclassifiable with current immunohistochemical and molecular approaches. However, DNA methylation profiling allowed us to classify this neoplasia as small blue round cell tumor with CIC alterations. The patient was treated with neoadjuvant chemotherapy followed by complete surgical resection and adjuvant chemotherapy. After 22 months, the patient is disease-free and in good clinical condition. To put our experience in context, we conducted a literature review, analyzing current knowledge and state-of-the-art diagnosis, prognosis, and clinical management of CIC rearranged sarcomas. Our findings further support the use of DNA methylation profiling as an important tool to improve diagnosis of non-Ewing small round cell tumors.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Mutação , Proteínas Repressoras/genética , Sarcoma de Células Pequenas/diagnóstico , Sarcoma/diagnóstico , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Diferenciação Celular , Criança , Terapia Combinada , Diagnóstico Diferencial , Feminino , Humanos , Prognóstico , Sarcoma/genética , Sarcoma/terapia , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma de Células Pequenas/genética , Sarcoma de Células Pequenas/terapia
20.
Gynecol Oncol ; 157(2): 357-366, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32156473

RESUMO

OBJECTIVE: Genomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS. METHODS: A retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed. RESULTS: We identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD. CONCLUSIONS: Alterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.


Assuntos
Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma/genética , Neoplasias Uterinas/genética , Adulto , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Amplificação de Genes , Rearranjo Gênico , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/patologia , Neoplasias Uterinas/patologia
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