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1.
Mol Cancer ; 23(1): 123, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849845

RESUMO

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.


Assuntos
Neoplasias Encefálicas , Glioma , Proteínas Proto-Oncogênicas c-met , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Glioma/patologia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/terapia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Camundongos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Feminino , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Modelos Animais de Doenças , Criança , Gradação de Tumores , Anilidas/farmacologia , Imidazóis , Triazinas
2.
Cancer Metastasis Rev ; 42(2): 367-388, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37119408

RESUMO

Recurrent, clonal somatic mutations in histone H3 are molecular hallmarks that distinguish the genetic mechanisms underlying pediatric and adult high-grade glioma (HGG), define biological subgroups of diffuse glioma, and highlight connections between cancer, development, and epigenetics. These oncogenic mutations in histones, now termed "oncohistones", were discovered through genome-wide sequencing of pediatric diffuse high-grade glioma. Up to 80% of diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) and diffuse glioma arising in other midline structures including thalamus or spinal cord, contain histone H3 lysine 27 to methionine (K27M) mutations or, rarely, other alterations that result in a depletion of H3K27me3 similar to that induced by H3 K27M. This subgroup of glioma is now defined as diffuse midline glioma, H3K27-altered. In contrast, histone H3 Gly34Arg/Val (G34R/V) mutations are found in approximately 30% of diffuse glioma arising in the cerebral hemispheres of older adolescents and young adults, now classified as diffuse hemispheric glioma, H3G34-mutant. Here, we review how oncohistones modulate the epigenome and discuss the mutational landscape and invasive properties of histone mutant HGGs of childhood. The distinct mechanisms through which oncohistones and other mutations rewrite the epigenetic landscape provide novel insights into development and tumorigenesis and may present unique vulnerabilities for pHGGs. Lessons learned from these rare incurable brain tumors of childhood may have broader implications for cancer, as additional high- and low-frequency oncohistone mutations have been identified in other tumor types.


Assuntos
Neoplasias Encefálicas , Glioma Pontino Intrínseco Difuso , Glioma , Adolescente , Adulto Jovem , Humanos , Criança , Histonas/genética , Glioma/genética , Glioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Epigênese Genética , Mutação
3.
Acta Neuropathol ; 145(1): 49-69, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36437415

RESUMO

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.


Assuntos
Neoplasias do Sistema Nervoso Central , Tumores Neuroectodérmicos Primitivos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Proteínas de Ciclo Celular/genética , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Tumores Neuroectodérmicos Primitivos/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Via de Sinalização Wnt/genética
4.
Bioinformatics ; 36(4): 1270-1272, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31566663

RESUMO

MOTIVATION: The traditional reads per million normalization method is inappropriate for the evaluation of ChIP-seq data when treatments or mutations have global effects. Changes in global levels of histone modifications can be detected with exogenous reference spike-in controls. However, most ChIP-seq studies overlook the normalization that must be corrected with spike-in. A method that retrospectively renormalizes datasets without spike-in is lacking. RESULTS: ChIPseqSpikeInFree is a novel ChIP-seq normalization method to effectively determine scaling factors for samples across various conditions and treatments, which does not rely on exogenous spike-in chromatin or peak detection to reveal global changes in histone modification occupancy. Application of ChIPseqSpikeInFree on five datasets demonstrates that this in silico approach reveals a similar magnitude of global changes as the spike-in method does. AVAILABILITY AND IMPLEMENTATION: St. Jude Cloud (https://pecan.stjude.cloud/permalink/spikefree) and St. Jude Github ( https://github.com/stjude/ChIPseqSpikeInFree). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Sequenciamento de Cromatina por Imunoprecipitação , Código das Histonas , Cromatina , Imunoprecipitação da Cromatina , Estudos Retrospectivos , Análise de Sequência de DNA
5.
Acta Neuropathol ; 140(2): 209-225, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32519082

RESUMO

Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children's Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.


Assuntos
Neoplasias Encefálicas , Modelos Animais de Doenças , Xenoenxertos , Animais , Criança , Humanos , Camundongos
6.
Acta Neuropathol ; 137(1): 123-137, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30267146

RESUMO

Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric patient, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were present in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only. For the EGFR-carrying double minutes, we found a secondary somatic deletion in all copies at relapse, after erlotinib treatment. However, the somatic mutation was present at very low frequency at diagnosis, suggesting potential resistance to the EGFR inhibitor. This mutation caused an in-frame RNA transcript to skip exon 16, a novel transcript isoform absent in EST database, as well as about 700 RNA-seq of normal brains that we reviewed. We observed similar patterns involving longitudinal copy number shift of double minutes in another four pairs (diagnosis/relapse) of adult glioblastoma. Overall, in three of five paired tumor samples, we found that although the same oncogenes were amplified at diagnosis and relapse, they were amplified on different double minutes. Our results suggest that double minutes readily evolve, increasing tumor heterogeneity rapidly. Understanding patterns of double minute evolution can shed light on future therapeutic solutions to brain tumors carrying such variants.


Assuntos
Neoplasias Encefálicas/diagnóstico , Encéfalo/patologia , Glioblastoma/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Genômica , Glioblastoma/diagnóstico , Glioma/genética , Humanos , Masculino , Mutação/genética , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva
7.
Acta Neuropathol ; 137(4): 637-655, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30770999

RESUMO

Histone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Comparisons of matched DIPG xenografts with and without K27M knockdown allowed identification of mutation-specific effects on the transcriptome and epigenome. The resulting transcriptional changes recapitulate expression signatures from K27M primary DIPG tumors and are strongly enriched for genes associated with nervous system development. Integrated analysis of ChIP-seq and expression data showed that genes upregulated by the mutation are overrepresented in apparently bivalent promoters. Many of these targets are associated with more immature differentiation states. Expression profiles indicate K27M knockdown decreases proliferation and increases differentiation within lineages represented in DIPG. These data suggest that K27M-mediated loss of H3K27me3 directly regulates a subset of genes by releasing poised promoters, and contributes to tumor phenotype and growth by limiting differentiation. The delayed tumor growth associated with knockdown of H3 K27M provides evidence that this highly recurrent mutation is a relevant therapeutic target.


Assuntos
Neoplasias do Tronco Encefálico/genética , Diferenciação Celular/genética , Glioma Pontino Intrínseco Difuso/genética , Histonas/genética , Mutação , Animais , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Glioma Pontino Intrínseco Difuso/patologia , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Camundongos
9.
Nat Methods ; 12(6): 527-30, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25938371

RESUMO

We developed Copy Number Segmentation by Regression Tree in Next Generation Sequencing (CONSERTING), an algorithm for detecting somatic copy-number alteration (CNA) using whole-genome sequencing (WGS) data. CONSERTING performs iterative analysis of segmentation on the basis of changes in read depth and the detection of localized structural variations, with high accuracy and sensitivity. Analysis of 43 cancer genomes from both pediatric and adult patients revealed novel oncogenic CNAs, complex rearrangements and subclonal CNAs missed by alternative approaches.


Assuntos
Variações do Número de Cópias de DNA/genética , DNA/genética , Genômica/métodos , Neoplasias/genética , Software , Adulto , Algoritmos , Criança , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Marcadores Genéticos , Genoma , Humanos
11.
Nature ; 488(7409): 43-8, 2012 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-22722829

RESUMO

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.


Assuntos
Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Meduloblastoma/classificação , Meduloblastoma/genética , Mutação/genética , Animais , Antígenos CD , Proteína de Ligação a CREB/genética , Caderinas/genética , Proteínas Cdh1 , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Linhagem da Célula , Neoplasias Cerebelares/patologia , Criança , Classe I de Fosfatidilinositol 3-Quinases , RNA Helicases DEAD-box/genética , Variações do Número de Cópias de DNA , DNA Helicases/genética , Análise Mutacional de DNA , Modelos Animais de Doenças , Genoma Humano/genética , Genômica , Proteínas Hedgehog/metabolismo , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Meduloblastoma/patologia , Metilação , Camundongos , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinases/genética , Fatores de Transcrição/genética , Proteínas Wnt/metabolismo , beta Catenina/genética
13.
Pediatr Blood Cancer ; 64(8)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28084680

RESUMO

A 4-year-old male presented with rapid-onset cranial nerve palsy and ataxia. Brain magnetic resonance imaging (MRI) revealed a pontine mass lesion with discordant conventional and advanced imaging. A stereotactic core biopsy revealed glioblastoma with immunostaining suggestive of histone H3K27M and TP53 mutation, consistent with diffuse intrinsic pontine glioma. MRI 3 months after radiotherapy revealed extensive new leptomeningeal metastatic disease involving both the supra- and infratentorial brain, as well as the imaged portion of the spine. Tissue procured at the time of needle biopsy has undergone striking in vivo expansion as an orthotopic xenograft.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/radioterapia , Glioblastoma/patologia , Glioblastoma/radioterapia , Carcinomatose Meníngea/patologia , Pré-Escolar , Progressão da Doença , Evolução Fatal , Humanos , Masculino
14.
J Pathol ; 238(1): 21-30, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26279473

RESUMO

Inactivation of the ARID1A tumour suppressor gene is frequent in ovarian endometrioid (OEC) and clear cell (OCCC) carcinomas, often in conjunction with mutations activating the PI3K-AKT and/or canonical Wnt signalling pathways. Prior work has shown that conditional bi-allelic inactivation of the Apc and Pten tumour suppressor genes in the mouse ovarian surface epithelium (OSE) promotes outgrowth of tumours that reflect the biological behaviour and gene expression profiles of human OECs harbouring comparable Wnt and PI3K-AKT pathway defects, although the mouse tumours are more poorly differentiated than their human tumour counterparts. We found that conditional inactivation of one or both Arid1a alleles in OSE concurrently with Apc and Pten inactivation unexpectedly prolonged the survival of tumour-bearing mice and promoted striking epithelial differentiation of the cancer cells, resulting in morphological features akin to those in human OECs. Enhanced epithelial differentiation was linked to reduced expression of the mesenchymal markers N-cadherin and vimentin, and increased expression of the epithelial markers Crb3 and E-cadherin. Global gene expression profiling showed enrichment for genes associated with mesenchymal-epithelial transition in the Arid1a-deficient tumours. We also found that an activating (E545K) Pik3ca mutation, unlike Pten inactivation or Pik3ca H1047R mutation, cannot cooperate with Arid1a loss to promote ovarian cancer development in the mouse. Our results indicate that the Arid1a tumour suppressor gene has a key role in regulating OEC differentiation, and paradoxically the mouse cancers with more initiating tumour suppressor gene defects had a less aggressive phenotype than cancers arising from fewer gene alterations. Microarray data have been deposited in NCBI's Gene Expression Omnibus (GSE67695).


Assuntos
Proteínas de Ligação a DNA/genética , Genes APC , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/genética , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Animais , Western Blotting , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Diferenciação Celular/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Epitélio/patologia , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Análise Serial de Tecidos , Fatores de Transcrição , Transcriptoma
15.
Genes Dev ; 23(14): 1619-24, 2009 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-19605683

RESUMO

Loss of PTEN causes unregulated activation of downstream components of phosphatidylinositol 3-kinase (PI3K) signaling, including PDK1, and disrupts normal nervous system development and homeostasis. We tested the contribution of Pdk1 to the abnormalities induced by Pten deletion in the brain. Conditional deletion of Pdk1 caused microcephaly. Combined deletion of Pdk1 and Pten rescued hypertrophy, but not migration defects of Pten-deficient neurons. Pdk1 inactivation induced strikingly different effects on the regulation of phosphorylated Akt in glia versus neurons. Our results show Pdk1-dependent and Pdk1-independent abnormalities in Pten-deficient brains, and demonstrate cell type specific differences in feedback regulation of the ubiquitous PI3K pathway.


Assuntos
Encéfalo/metabolismo , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Animais , Movimento Celular , Núcleo Celular/metabolismo , Cerebelo/metabolismo , Classe I de Fosfatidilinositol 3-Quinases , Síndrome da Deleção Distal 11q de Jacobsen , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
16.
Glia ; 64(6): 879-95, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26638183

RESUMO

Brain tumors represent the most common solid tumor of childhood, with gliomas comprising the largest fraction of these cancers. Several features distinguish them from their adult counterparts, including their natural history, causative genetic mutations, and brain locations. These unique properties suggest that the cellular and molecular etiologies that underlie their development and maintenance might be different from those that govern adult gliomagenesis and growth. In this review, we discuss the genetic basis for pediatric low-grade and high-grade glioma in the context of developmental neurobiology, and highlight the differences between histologically-similar tumors arising in children and adults.


Assuntos
Neoplasias Encefálicas/genética , Predisposição Genética para Doença , Glioma/genética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Animais , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos
17.
Am J Pathol ; 185(4): 1104-13, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25698082

RESUMO

PTEN and PIK3CA mutations occur with high frequency in uterine endometrioid carcinoma (UEC). Although PTEN mutations are present in complex atypical hyperplasia and carcinoma, PIK3CA mutations are restricted to carcinoma. We generated mouse models harboring Pten loss and/or activated Pik3ca in the endometrial epithelium to investigate their respective roles in the pathogenesis of UEC. Presence of an activated mutant Pik3ca on the background of Pten loss led to aggressive disease, with 100% of mice exhibiting carcinoma. Expression of Pik3ca with E545K mutation alone was unable to cause hyperplasia or cancer in the uterus and did not activate Akt as effectively as Pten deletion in short-term cultures of mouse endometrial epithelium, likely explaining the lack of phenotype in vivo. We also report that nuclear localization of FOXO1 correlated with PTEN mutational status irrespective of the PIK3CA status in endometrial cancer cell lines. Furthermore, gene expression profiles resulting from Pten loss or activation of Pik3ca in primary mouse endometrial epithelial cells exhibit minimal overlap. Thus, Pten and Pik3ca have distinct consequences on the activation of the phosphatidylinositol 3-kinase pathway in endometrial epithelium and are likely to affect other nonoverlapping cellular mechanisms involved in the development and progression of the most common type of uterine cancer.


Assuntos
Alelos , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Deleção de Genes , Proteínas Mutantes/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias do Endométrio/genética , Ativação Enzimática , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recombinação Genética/genética , Análise de Sequência de RNA , Transdução de Sinais
18.
Acta Neuropathol ; 131(6): 833-45, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26810070

RESUMO

Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.


Assuntos
Neoplasias Encefálicas/patologia , Genes myb , Predisposição Genética para Doença , Glioma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Adulto , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA , Feminino , Ganglioglioma/genética , Ganglioglioma/patologia , Glioma/patologia , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas Proto-Oncogênicas/genética , Proteínas de Ligação a RNA , Transativadores/genética , Fatores de Transcrição , Adulto Jovem
19.
Development ; 139(18): 3422-31, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22874917

RESUMO

Neuronal precursors, generated throughout life in the subventricular zone, migrate through the rostral migratory stream to the olfactory bulb where they differentiate into interneurons. We found that the PI3K-Akt-mTorc1 pathway is selectively inactivated in migrating neuroblasts in the subventricular zone and rostral migratory stream, and activated when these cells reach the olfactory bulb. Postnatal deletion of Pten caused aberrant activation of the PI3K-Akt-mTorc1 pathway and an enlarged subventricular zone and rostral migratory stream. This expansion was caused by premature termination of migration and differentiation of neuroblasts and was rescued by inhibition of mTorc1. This phenotype is reminiscent of lamination defects caused by Pten deletion in developing brain that were previously described as defective migration. However, live imaging in acute slices showed that Pten deletion did not cause a uniform defect in the mechanics of directional neuroblast migration. Instead, a subpopulation of Pten-null neuroblasts showed minimal movement and altered morphology associated with differentiation, whereas the remainder showed unimpeded directional migration towards the olfactory bulb. Therefore, migration defects of Pten-null neurons might be secondary to ectopic differentiation.


Assuntos
Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Neurônios/citologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas/metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Diferenciação Celular/genética , Movimento Celular/genética , Eletroporação , Técnicas In Vitro , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos , Neurônios/metabolismo , PTEN Fosfo-Hidrolase/genética , Proteínas/genética , Serina-Treonina Quinases TOR
20.
Am J Pathol ; 182(4): 1391-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23499052

RESUMO

A dualistic pathway model of ovarian carcinoma (OvCA) pathogenesis has been proposed: type I OvCAs are low grade, genetically stable, and relatively more indolent than type II OvCAs, most of which are high-grade serous carcinomas. Endometrioid OvCA (EOC) is a prototypical type I tumor, often harboring mutations that affect the Wnt and phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathways. Molecular and histopathologic analyses indicate type I and II OvCAs share overlapping features, and a subset of EOCs may undergo type I→type II progression accompanied by acquisition of somatic TP53 or PIK3CA mutations. We used a murine model of EOC initiated by conditional inactivation of the Apc and Pten tumor suppressor genes to investigate mutant Trp53 or Pik3ca alleles as key drivers of type I→type II OvCA progression. In the mouse EOC model, the presence of somatic Trp53 or Pik3ca mutations resulted in shortened survival and more widespread metastasis. Activation of mutant Pik3ca alone had no demonstrable effect on the ovarian surface epithelium but resulted in papillary hyperplasia when coupled with Pten inactivation. Our findings indicate that the adverse prognosis associated with TP53 and PIK3CA mutations in human cancers can be functionally replicated in mouse models of type I→type II OvCA progression. Moreover, the models should represent a robust platform for assessment of the contributions of Trp53 or Pik3ca defects in the response of EOCs to conventional and targeted drugs.


Assuntos
Progressão da Doença , Mutação de Sentido Incorreto/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/genética , Proteína Supressora de Tumor p53/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Transformação Celular Neoplásica/patologia , Classe I de Fosfatidilinositol 3-Quinases , Modelos Animais de Doenças , Endométrio/patologia , Células Epiteliais/patologia , Feminino , Humanos , Hiperplasia , Camundongos , Proteínas Mutantes/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Ovarianas/enzimologia , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Análise de Sobrevida , Proteína Supressora de Tumor p53/metabolismo
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