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1.
Nat Commun ; 9(1): 3184, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093639

RESUMO

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

3.
Nat Genet ; 47(10): 1200-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26343384

RESUMO

While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Sarcoma/genética , Neoplasias Torácicas/genética , Fatores de Transcrição/genética , Transcrição Genética , Adulto , Humanos
4.
Cancer Res ; 72(17): 4494-503, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22930730

RESUMO

Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC-ß (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of-concept for PRKCB as a promising therapeutic target in Ewing sarcoma.


Assuntos
Proteínas de Ligação a Calmodulina/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteína Quinase C/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Animais , Proteínas de Ligação a Calmodulina/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Histonas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Proteínas de Fusão Oncogênica/genética , Fosforilação , Proteína Quinase C/metabolismo , Proteína Quinase C beta , Proteína Proto-Oncogênica c-fli-1/genética , Interferência de RNA , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética
5.
Nat Genet ; 44(4): 461-6, 2012 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-22387997

RESUMO

The identification of subtype-specific translocations has revolutionized the diagnostics of sarcoma and has provided new insight into oncogenesis. We used RNA-seq to investigate samples from individuals diagnosed with small round cell tumors of bone, possibly Ewing sarcoma, but which lacked the canonical EWSR1-ETS translocation. A new fusion was observed between BCOR (encoding the BCL6 co-repressor) and CCNB3 (encoding the testis-specific cyclin B3) on the X chromosome. RNA-seq results were confirmed by RT-PCR and through cloning of the tumor-specific genomic translocation breakpoints. In total, 24 BCOR-CCNB3-positive tumors were identified among a series of 594 sarcoma cases. Gene profiling experiments indicated that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this subgroup of sarcoma and that overexpression of BCOR-CCNB3 or of truncated CCNB3 activates S phase in NIH3T3 cells. Thus, the intrachromosomal X-chromosome fusion described here represents a new subtype of bone sarcoma caused by a newly identified gene fusion mechanism.


Assuntos
Neoplasias Ósseas/genética , Ciclina B/genética , Fusão Gênica , Proteínas de Fusão Oncogênica/genética , Osteossarcoma/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma/genética , Adolescente , Adulto , Animais , Sequência de Bases , Biomarcadores Tumorais/genética , Linhagem Celular , Criança , Cromossomos Humanos X/genética , Ciclina B/biossíntese , Ciclina B/metabolismo , Feminino , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Células NIH 3T3 , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteínas Repressoras/biossíntese , Proteínas Repressoras/metabolismo , Sarcoma/patologia , Sarcoma de Ewing/genética , Análise de Sequência de DNA , Translocação Genética , Adulto Jovem
6.
Nat Genet ; 44(3): 323-7, 2012 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-22327514

RESUMO

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.


Assuntos
Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 1/genética , Proteínas de Ligação a DNA/genética , Proteína 2 de Resposta de Crescimento Precoce/genética , Predisposição Genética para Doença/genética , Sarcoma de Ewing/genética , França , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos/genética , Humanos , Modelos Logísticos , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Sarcoma de Ewing/etnologia
7.
Diagn Cytopathol ; 40(1): 19-25, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22180234

RESUMO

Fine-needle aspiration (FNA) followed by a core-needle biopsy during general anesthesia is a method for diagnosing pediatric tumors in our Institute. To complete the diagnosis in the case of round cell sarcomas, cytology material is also used for genomic analyses, that is, karyotyping and molecular biology-derived techniques. Fifty primary Ewing sarcomas/peripheral neuroectodermal tumors (ES/PNET) in 50 patients were sampled. Cytological diagnoses were "malignant" in all cases and accurate (ES/PNET) in 46 (92%). Two (4%) cases were misdiagnosed as neuroblastoma, and two others (4%) as rhabdomyosarcoma and nephroblastoma. No suspicious or false-negative results were rendered. Karyotyping was performed in 20 (40%) cases and was interpretable in 17 cases but not in three cases. Molecular search for ES/PNET fusion transcripts were performed in all cases and were detected in 44 (88%) cases, but not in six (12%) cases. In conclusion, FNA assisted by genomic techniques is powerful methods to accurate diagnose ES/PNET.


Assuntos
Biópsia por Agulha Fina , Tumores Neuroectodérmicos Primitivos Periféricos/diagnóstico , Sarcoma de Ewing/diagnóstico , Cariótipo Anormal , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Tumores Neuroectodérmicos Primitivos Periféricos/genética , Reação em Cadeia da Polimerase em Tempo Real , Sarcoma de Ewing/genética , Adulto Jovem
8.
J Med Genet ; 47(12): 859-62, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20805368

RESUMO

BACKGROUND: Epidermal nevus (EN) is a congenital disorder characterised by hyperpigmented epidermal thickening following a Blaschko's line. It is due to somatic mutations in either FGFR3 or PIK3CA in half of the cases, and remains of unknown genetic origin in the other half. EN is also seen as part of complex developmental disorders or in association with bladder carcinomas, also related to FGFR3 and PIK3CA mutations. Mosaic mutations of these genes have been occasionally found in syndromic EN. CASE REPORT: The co-occurrence of EN, rhabdomyosarcoma, polycystic kidneys and growth retardation in an infant is described. RESULTS: An oncogenic G12D KRAS mutation was detected in both the epidermal component of the EN and in the rhabdomyosarcoma but not in the dermal component of the EN lesion or in unaffected tissues, including normal skin or blood. CONCLUSION: This report shows for the first time that a KRAS mutation in epiderma causes EN. Observation of the same G12D KRAS mutation in two distinct regions of the body strongly suggests a somatic mosaicism. Finally, this report highlights the potentially underestimated importance of mosaic oncogene mutations in childhood cancers.


Assuntos
Predisposição Genética para Doença , Mosaicismo , Mutação/genética , Doenças Renais Policísticas/genética , Proteínas Proto-Oncogênicas/genética , Rabdomiossarcoma/genética , Proteínas ras/genética , Substituição de Aminoácidos/genética , Sequência de Bases , Feminino , Dosagem de Genes/genética , Humanos , Lactente , Recém-Nascido , Dados de Sequência Molecular , Nevo Sebáceo de Jadassohn/complicações , Nevo Sebáceo de Jadassohn/genética , Nevo Sebáceo de Jadassohn/patologia , Fenótipo , Doenças Renais Policísticas/complicações , Doenças Renais Policísticas/patologia , Proteínas Proto-Oncogênicas p21(ras) , Rabdomiossarcoma/complicações , Rabdomiossarcoma/patologia
9.
J Clin Oncol ; 28(12): 1982-8, 2010 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-20308673

RESUMO

PURPOSE EWS-ETS fusion genes are the driving force in Ewing's sarcoma pathogenesis. Because of the variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. Since previous retrospective studies suggested prognostic differences among patients expressing different EWS-FLI1 fusion types, the impact of fusion RNA architecture on disease progression and relapse was studied prospectively within the Euro-E.W.I.N.G. 99 clinical trial. PATIENTS AND METHODS Among 1,957 patients who registered before January 1, 2007, 703 primary tumors were accessible for the molecular biology study. Fusion type was assessed by polymerase chain reaction on frozen (n = 578) or paraffin-embedded materials (n = 125). The primary end point was the time to disease progression or relapse. Results After exclusion of noninformative patients, 565 patients were entered into the prognostic factor analysis comparing type 1 (n = 296), type 2 (n = 133), nontype 1/nontype 2 EWS-FLI1 (n = 91) and EWS-ERG fusions (n = 45). Median follow-up time was 4.5 years. The distribution of sex, age, tumor volume, tumor site, disease extension, or histologic response did not differ between the four fusion type groups. We did not observe any significant prognostic value of the fusion type on the risk of progression or relapse. The only slight difference was that the risk of progression or relapse associated with nontype 1/nontype 2 EWS-FLI1 fusions was 1.38 (95% CI, 0.96 to 2.0) times higher than risk associated with other fusion types, but it was not significant (P = .10). CONCLUSION In contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit for type 1 EWS-FLI1 fusions.


Assuntos
Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Sarcoma de Ewing/genética , Fatores de Transcrição/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Distribuição de Qui-Quadrado , Progressão da Doença , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia , Inclusão em Parafina , Fenótipo , Modelos de Riscos Proporcionais , Estudos Prospectivos , Proteína EWS de Ligação a RNA , Radioterapia Adjuvante , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medição de Risco , Fatores de Risco , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/secundário , Sarcoma de Ewing/terapia , Transplante de Células-Tronco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Ann Diagn Pathol ; 14(1): 56-9, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20123459

RESUMO

A 39-year-old woman presented with an incidentally discovered mass of the left adrenal fossa. Computed tomography and magnetic resonance imaging did not show any other lesion. Histologically, this mass was composed of a dense proliferation of spindle cells with a fibrosarcomatous-like pattern. Immunohistochemistry using anticytokeratin showed some epithelial cells within the tumor. The diagnosis of primitive synovial sarcoma of the left adrenal fossa was confirmed by the presence of the characteristic t(X;18) translocation. Despite radiotherapy, several chemotherapies, and 2 other surgical resections, the patient died 30 months after the initial diagnosis. To our knowledge, this report constitutes the first described case of synovial sarcoma arising in the adrenal gland.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/patologia , Imagem por Ressonância Magnética , Sarcoma Sinovial/patologia , Adulto , Biópsia , Evolução Fatal , Feminino , Humanos , Imuno-Histoquímica
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