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1.
J Clin Invest ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805011

RESUMO

BACKGROUND: DICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist. METHODS: Whole exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome wide analyses were performed on 13 tissue samples from familial and non-familial DGCR8-E518K positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTC) and Wilms Tumors. MiRNA profiles of four tissue types were compared, and sequencing of miRNA, pre-miRNA and mRNA was performed in a subset of 9 schwannomas, four of which harbor DGCR8-E518K. RESULTS: We identified c.1552G>A;p.E518K in DGCR8, a microprocessor located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms Tumors and has been identified in two PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTC, MNG, schwannomas and Wilms Tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons. CONCLUSIONS: We identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.Funded by CIHR, Compute Canada, Alex's Lemonade Stand Foundation, and the Mia Neri Foundation for Childhood Cancer.

2.
Nat Genet ; 51(12): 1702-1713, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768071

RESUMO

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Humanos , Lactente , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Prosencéfalo/citologia , Prosencéfalo/embriologia , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Análise de Célula Única
3.
Life Sci Alliance ; 2(4)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31331983

RESUMO

Chromatin immunoprecipitation (ChIP) followed by next generation sequencing (ChIP-Seq) is a powerful technique to study transcriptional regulation. However, the requirement of millions of cells to generate results with high signal-to-noise ratio precludes it in the study of small cell populations. Here, we present a tagmentation-assisted fragmentation ChIP (TAF-ChIP) and sequencing method to generate high-quality histone profiles from low cell numbers. The data obtained from the TAF-ChIP approach are amenable to standard tools for ChIP-Seq analysis, owing to its high signal-to-noise ratio. The epigenetic profiles from TAF-ChIP approach showed high agreement with conventional ChIP-Seq datasets, thereby underlining the utility of this approach.


Assuntos
/métodos , Drosophila/genética , Histonas/metabolismo , Animais , Epigênese Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células K562 , Razão Sinal-Ruído , Software , Sequenciamento Completo do Genoma
4.
Fam Cancer ; 18(2): 161-163, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30284660

RESUMO

One of a pair of monozygous twins was diagnosed and died of small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) at the age of 30 years. Her sister remained unaffected and was very concerned about her risk for developing SCCOHT. By performing comprehensive molecular analysis using whole exome sequencing (WES) approach, we showed that the deceased twin's tumour has bi-allelic somatic genetic defects (a pathogenic frameshift deletion in SMARCA4 and LOH on chr19p). Results of WES of constitutional DNA from her unaffected sister were confirmatory. Based on our findings, we concluded that the living twin is not at risk for SCCOHT and does not need to consider preventive oophorectomy.


Assuntos
Carcinoma de Células Pequenas/diagnóstico , Doenças em Gêmeos/diagnóstico , Hipercalcemia/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adulto , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , DNA Helicases/genética , Análise Mutacional de DNA , Doenças em Gêmeos/genética , Doenças em Gêmeos/patologia , Evolução Fatal , Feminino , Humanos , Hipercalcemia/genética , Hipercalcemia/patologia , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/patologia , Fatores de Transcrição/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma
7.
Cancer Cell ; 32(5): 684-700.e9, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29107533

RESUMO

Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.


Assuntos
Células-Tronco Embrionárias/metabolismo , Glioma/genética , Histonas/genética , Células-Tronco Neurais/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Proteína Supressora de Tumor p53/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Mutação , Gradação de Tumores , Invasividade Neoplásica , Interferência de RNA , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo
8.
Nat Genet ; 49(5): 780-788, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28394352

RESUMO

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.


Assuntos
Neoplasias Cerebelares/genética , Regulação Neoplásica da Expressão Gênica , Meduloblastoma/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Análise por Conglomerados , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Estudo de Associação Genômica Ampla , Humanos , Mutação INDEL , Masculino , Meduloblastoma/patologia , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Fam Cancer ; 16(3): 395-399, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27866340

RESUMO

Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40 years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.


Assuntos
Carcinoma de Células Pequenas/genética , DNA Helicases/genética , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Adulto , Feminino , Humanos , Hipercalcemia , Mutação , Linhagem , Adulto Jovem
10.
Pediatr Blood Cancer ; 64(2): 275-278, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27718322

RESUMO

A cerebellar pilocytic astrocytoma (PA) in a child recurred first with a PA histology and then with features of a ganglioglioma (GG). Molecular genetic analyses of the tumors confirmed a BRAF V600E mutation in all. They also all harbored a T202M mutation in ERK1, a kinase downstream of BRAF that is implicated in glial versus neuronal differentiation. The GG sample contained several variants that were not present in the PA samples; in particular, it had a truncating mutation in MAP2. These findings not only underscore the role of BRAF as oncogenic driver but also suggest that other genes may influence tumor morphology.


Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/etiologia , Neoplasias Cerebelares/genética , Ganglioglioma/etiologia , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/complicações , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/patologia , Pré-Escolar , Análise Mutacional de DNA , Feminino , Ganglioglioma/patologia , Humanos , Recidiva Local de Neoplasia , Prognóstico
11.
Acta Neuropathol Commun ; 4(1): 127, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27931265

RESUMO

Abnormally elevated hippocampal Caspase-6 (Casp6) activity is intimately associated with age-related cognitive impairment in humans and in mice. In humans, these high levels of Casp6 activity are initially localized in the entorhinal cortex, the area of the brain first affected by the formation of neurofibrillary tangles, according to Braak staging. The reason for the high vulnerability of entorhinal cortex neurons to neurofibrillary tangle pathology and Casp6 activity is unknown. Casp6 activity is involved in axonal degeneration, therefore, one possibility to explain increased vulnerability of the entorhinal cortex neurons would be that the afferent neurons of the olfactory bulb, some of which project their axons to the entorhinal cortex, are equally degenerating. To examine this possibility, we examined the presence of Casp6 activity, neurofibrillary tangle formation and amyloid deposition by immunohistochemistry with neoepitope antisera against the p20 subunit of active Casp6 and Tau cleaved by Casp6 (Tau∆Casp6), phosphorylated Tau paired helical filament (PHF-1) antibodies and anti-ß-amyloid antiserum, respectively, in brains from individuals with no or mild cognitive impairment and Alzheimer disease (AD) dementia. Co-localization of Casp6 activity, PHF-1 and ß-amyloid was detected mostly in the anterior olfactory nucleus (AON) of the olfactory bulb. The levels of active Casp6 in the AON, which were the highest in the AD brains, correlated with PHF-1 levels, but not with ß-amyloid levels. AON Tau∆Casp6 levels correlated with entorhinal cortex Casp6 activity and PHF-1 levels. Multiple regression analyses demonstrated that AON Casp6 activity was associated with lower global cognitive function, mini mental state exam, episodic memory and semantic memory scores. These results suggest that AON Casp6 activity could lead to Casp6-mediated degeneration in the entorhinal cortex, but cannot exclude the possibilities that entorhinal cortex degeneration signals degeneration in the AON or that the pathologies occur in both regions independently. Nevertheless, AON Casp6 activity reflects that of the entorhinal cortex.


Assuntos
Doença de Alzheimer/enzimologia , Caspase 6/metabolismo , Disfunção Cognitiva/enzimologia , Bulbo Olfatório/enzimologia , Córtex Olfatório/enzimologia , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Imuno-Histoquímica , Masculino , Memória/fisiologia , Entrevista Psiquiátrica Padronizada , Testes Neuropsicológicos , Bulbo Olfatório/patologia , Córtex Olfatório/patologia , Proteínas do Grupo Polycomb/metabolismo , Análise de Regressão , Índice de Gravidade de Doença , Proteínas tau/metabolismo
12.
Cancer Cell ; 30(6): 891-908, 2016 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-27960086

RESUMO

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Cromatina/genética , Epigenômica/métodos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Metilação de DNA , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Humanos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Tumor Rabdoide/tratamento farmacológico , Teratoma/tratamento farmacológico
13.
J Clin Oncol ; 34(19): 2206-11, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27001570

RESUMO

PURPOSE: Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. PATIENTS AND METHODS: We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. RESULTS: All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti-programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. CONCLUSION: This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Glioblastoma/genética , Mutação , Síndromes Neoplásicas Hereditárias/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Humanos , Imagem por Ressonância Magnética , Masculino , Nivolumabe
14.
Pediatr Blood Cancer ; 63(7): 1272-5, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26928971

RESUMO

Anaplastic sarcoma of kidney (ASK) is a rare neoplasm recently associated with DICER1 mutations. We report a child with germline DICER1 mutation who developed ASK in preexisting septated renal cysts, which were likely cystic nephroma. From age 2.5 to 6 years, sonographic imaging illustrated changes in the size and number of renal cysts, followed at age 8.8 years by a mass, pathologically an ASK. Lung cysts resected in infancy were diagnosed retrospectively as pleuropulmonary blastoma. Both tumors had acquired somatic DICER1 mutations. Ultrasonographic evolution of renal cysts to ASK has not previously been documented. Children with both pulmonary and renal cysts are candidates for DICER1 mutation testing.


Assuntos
Cistos , RNA Helicases DEAD-box/genética , Doenças Genéticas Inatas , Neoplasias Renais , Blastoma Pulmonar , Ribonuclease III/genética , Sarcoma , Criança , Pré-Escolar , Cistos/genética , Cistos/patologia , Cistos/cirurgia , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/cirurgia , Humanos , Lactente , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Blastoma Pulmonar/genética , Blastoma Pulmonar/patologia , Blastoma Pulmonar/cirurgia , Sarcoma/genética , Sarcoma/patologia , Sarcoma/cirurgia , Síndrome
15.
J Clin Endocrinol Metab ; 101(5): 1927-30, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26982009

RESUMO

CONTEXT: Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) with a female preponderance. CASE DESCRIPTION: A 4-year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 µg/L; normal, <18 µg/L), IGF-1 (745 µg/L; normal, 64-369 µg/L), and fasting GH > 35.0 µg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 × 15 × 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality. CONCLUSIONS: Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary.


Assuntos
Duplicação Gênica , Gigantismo/genética , Hipófise/diagnóstico por imagem , Receptores Acoplados a Proteínas-G/genética , Cabergolina , Pré-Escolar , Ergolinas/uso terapêutico , Gigantismo/diagnóstico por imagem , Gigantismo/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino
16.
Acta Neuropathol ; 131(6): 847-63, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26920151

RESUMO

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.


Assuntos
Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA/genética , Glioma/genética , Mutação/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Adulto , Feminino , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Proteínas Proto-Oncogênicas B-raf/genética , Adulto Jovem
17.
Oncotarget ; 6(31): 31844-56, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26378811

RESUMO

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.


Assuntos
Aneuploidia , Astrocitoma/classificação , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/classificação , Adulto , Fatores Etários , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Mutação/genética , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
18.
Lancet Oncol ; 16(5): 569-82, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25882982

RESUMO

BACKGROUND: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Genômica , Receptores Notch/biossíntese , Tumor Rabdoide/genética , Teratoma/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Masculino , Prognóstico , Receptores Notch/genética , Tumor Rabdoide/patologia , Fatores de Risco , Transdução de Sinais/genética , Teratoma/patologia
19.
Neuroradiol J ; 28(1): 46-50, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25924172

RESUMO

Intraventricular schwannoma in either infra or supratentorial location is an extremely rare tumor with less than 20 cases described in the literature to date. There is no consensus regarding the origin of this tumor. This paper describes an excised supratentorial schwannoma located on the wall of the left lateral ventricle. The relevant literature is reviewed. A 34-year-old man with no significant medical history presented with a recent episode of right focal motor seizures and weakness of the right lower extremity. Magnetic resonance imaging of the brain demonstrated a heterogeneous enhancing mass in the body of left lateral ventricle mass lesion with vasogenic edema in the adjacent brain parenchyma. The patient underwent a left frontoparietal parasagittal craniotomy with neuronavigational guidance to avoid damage to the primary motor cortex. The tumor originated from the ependymal layer and extended to the body of lateral ventricle. Complete surgical excision of the tumor was achieved. Intraventricular schwannomas are rare tumors amenable to complete surgical excision, having a good prognosis without the need for adjuvant therapy. The recognition of this benign and potentially curable neoplasm and its differentiation from other less favorable tumors is of obvious importance.


Assuntos
Ventrículos Laterais/patologia , Neurilemoma/diagnóstico , Neoplasias Supratentoriais/diagnóstico , Adulto , Humanos , Imagem por Ressonância Magnética , Masculino
20.
PLoS One ; 9(12): e114270, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25470254

RESUMO

Caspases play an important role in maintaining tissue homeostasis. Active Caspase-6 (Casp6) is considered a novel therapeutic target against Alzheimer disease (AD) since it is present in AD pathological brain lesions, associated with age-dependent cognitive decline, and causes age-dependent cognitive impairment in the mouse brain. However, active Casp6 is highly expressed and activated in normal human colon epithelial cells raising concerns that inhibiting Casp6 in AD may promote colon carcinogenesis. Furthermore, others have reported rare mutations of Casp6 in human colorectal cancers and an effect of Casp6 on apoptosis and metastasis of colon cancer cell lines. Here, we investigated the role of Casp6 in inflammation-associated azoxymethane/dextran sulfate sodium (AOM/DSS) colon cancer in Casp6-overexpressing and -deficient mice. In wild-type mice, AOM/DSS-induced tumors had significantly higher Casp6 mRNA, protein and activity levels compared to normal adjacent colon tissues. Increased human Casp6 or absence of Casp6 expression in mice colon epithelial cells did not change colonic tumor multiplicity, burden or distribution. Nevertheless, the incidence of hyperplasia was slightly reduced in human Casp6-overexpressing colons and increased in Casp6 null colons. Overexpression of Casp6 did not affect the grade of the tumors while all tumors in heterozygous or homozygous Casp6 null colons were high grade compared to only 50% high grade in wild-type mice. Casp6 levels did not alter cellular proliferation and apoptosis. These results suggest that Casp6 is unlikely to be involved in colitis-associated tumors.


Assuntos
Carcinogênese/metabolismo , Caspase 6/fisiologia , Colite/enzimologia , Neoplasias do Colo/enzimologia , Animais , Apoptose , Carcinogênese/imunologia , Proliferação de Células , Colite/imunologia , Colite/patologia , Colo/enzimologia , Colo/patologia , Neoplasias do Colo/etiologia , Neoplasias do Colo/imunologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
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