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1.
J Cancer Res Clin Oncol ; 146(3): 579-591, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32060643

RESUMO

PURPOSE: The WHO classification for IDH-mutant grade II and grade III astrocytoma may not be as prognostically meaningful as expected. We aimed to develop a novel classification system based on the DNA damage response signature. METHODS: We developed the gene signature of DNA damage response with 115 samples from The Cancer Genome Atlas (TCGA) database. The dataset from Chinese Glioma Genome Atlas (CGGA) database with 41 samples was used as the validation set. Lasso Cox regression model was applied for selection of the best signature. Gene set enrichment analysis (GSEA) and gene ontology (GO) analysis were implemented to reveal its biological phenotype. RESULTS: A two-gene DNA damage response signature (RAD18, MSH2) was developed using the lasso Cox regression model based on the TCGA dataset. Its prognostic efficiency was validated in the CGGA cohort. The result of Cox regression analysis showed that the signature has a better predictive accuracy than the WHO grade. The risk score was an independent prognostic factor for the overall survival of the IDH-mutant grade II and grade III astrocytoma. GSEA and GO analysis confirmed enhanced processes related to DNA damage response in high-risk group. CONCLUSION: We developed a two-gene signature which can effectively predict the prognosis of patients with IDH-mutant grade II and grade III astrocytoma. It suggests a novel classification of astrocytoma with better prognostic accuracy based on the expression of DNA damage response genes.


Assuntos
Astrocitoma/classificação , Astrocitoma/genética , Dano ao DNA/genética , Transcriptoma , Adulto , Astrocitoma/mortalidade , Feminino , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Prognóstico
2.
Medicine (Baltimore) ; 99(3): e18880, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011515

RESUMO

INTRODUCTION: Pleomorphic xanthoastrocytomas (PXA) are rare, typically benign, slow-growing tumors that commonly occur in the cerebral hemispheres. We describe two cases of clinically aggressive PXA with uncommon locations; one was in the tectal plate, and the other had simultaneous multicentric lesions. PATIENT CONCERNS: The both cases presented with severe headache with no significant past medical history. DIAGNOSIS: PXA World Health Organization grade II were histopathologically diagnosed from surgically resected specimens, and immunohistochemical and sequence analysis revealed a high Ki-67 proliferative index and BRAF V600E mutation in both the cases. INTERVENTIONS: The first case presented with multicentric lesions and underwent partial resection, whereas the second case presented with a tectal plate tumor that was managed by gross total surgical resection. Strong 5-aminolevulinic acid (5-ALA)-induced fluorescence was observed in both the lesions. Postoperative radiotherapy plus concomitant and adjuvant temozolomide was administered to both the patients. OUTCOMES: Despite completing adjuvant chemo-radiotherapy, both the patients had local tumor recurrence at 2 and 5 months after the operation, respectively. CONCLUSION: The progressive clinical courses in our cases suggest that additional postoperative therapy should be considered during the treatment of PXA with a high Ki67 index, and that temozolomide with radiotherapy, followed by temozolomide maintenance therapy, may not prevent recurrence in such tumors. Importantly, our experience implies that unlike other subtypes of low grade gliomas, 5-ALA fluorescence is useful for intraoperative visualization of PXA.


Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Astrocitoma/diagnóstico por imagem , Astrocitoma/genética , Astrocitoma/terapia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Terapia Combinada , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Antígeno Ki-67/genética , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Neoplasia Residual/diagnóstico por imagem , Neoplasia Residual/genética , Neoplasia Residual/terapia , Proteínas Proto-Oncogênicas B-raf/genética , Adulto Jovem
3.
Nat Commun ; 10(1): 3731, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427603

RESUMO

Pilocytic astrocytoma (PA), the most common childhood brain tumor, is a low-grade glioma with a single driver BRAF rearrangement. Here, we perform scRNAseq in six PAs using methods that enabled detection of the rearrangement. When compared to higher-grade gliomas, a strikingly higher proportion of the PA cancer cells exhibit a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibit a progenitor-like phenotype with evidence of proliferation. These express a mitogen-activated protein kinase (MAPK) programme that was absent from higher-grade gliomas. Immune cells, especially microglia, comprise 40% of all cells in the PAs and account for differences in bulk expression profiles between tumor locations and subtypes. These data indicate that MAPK signaling is restricted to relatively undifferentiated cancer cells in PA, with implications for investigational therapies directed at this pathway.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Células-Tronco Neurais/citologia , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Neoplasias Encefálicas/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Microglia/patologia , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oligodendroglia/citologia , Proteínas de Fusão Oncogênica/metabolismo , Células Tumorais Cultivadas
4.
Brain Tumor Pathol ; 36(4): 135-143, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31324999

RESUMO

The genetic features of isocitrate dehydrogenase-wild-type (IDH-wt) lower-grade gliomas (LGGs; World Health Organization grades II and III) are not well defined. This study analyzed the genetic and other features of IDH-wt LGGs to develop a subclassification that can be used to predict their prognosis. Clinical, histopathological, and genetic features of 35 cases of diffuse IDH-wt astrocytoma and IDH-wt anaplastic astrocytoma were analyzed. The following genetic factors were examined: mutations of B-rapidly accelerated fibrosarcoma, telomerase reverse transcriptase promoter (TERTp), histone 3 family 3A, and alpha-thalassemia/mental retardation syndrome, X-linked; and copy number aberrations. In the univariate analysis, the following factors were associated with poor overall survival (OS): the histopathological diagnosis, TERTp mutation, the gain of chromosome 7 (+ 7), and the loss of chromosome 10q (- 10q). In the multivariate analysis, + 7, - 10q, and TERTp mutation were independent prognostic factors associated with poor OS. The median OS was significantly worse for patients who harbored at least one of these factors than for those without any of them (18.5 vs. 54.5 months, P = 0.002). The subclassification of IDH-wt LGGs according to the genetic factors + 7, - 10q, and TERTp mutation is potentially useful for predicting the prognosis.


Assuntos
Glioma/genética , Glioma/patologia , Isocitrato Desidrogenase/genética , Adulto , Idoso , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/genética , Feminino , Glioma/metabolismo , Histonas/genética , Humanos , Isocitrato Desidrogenase/metabolismo , Japão , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Regiões Promotoras Genéticas/genética , Telomerase/genética , Talassemia alfa/genética
5.
Clin Nucl Med ; 44(10): e581-e582, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348085

RESUMO

A variety of neoplastic and nonneoplastic conditions involve the corpus callosum, which may result in a "butterfly" appearance on conventional MRI. Typically, that pattern shows a bilateral and heterogeneous contrast enhancement of the lesion, occasionally with central nonenhancing areas indicating intralesional necrosis. In contrast, anaplastic gliomas may show only minimal or even a lack of contrast enhancement on MRI. We here report neuroimaging findings in a 69-year-old man with a "butterfly" pattern on dynamic FET [O-(2-[F]-fluoroethyl)-L-tyrosine] PET and the diagnosis of an anaplastic astrocytoma (WHO grade III; IDH-1/-2 wildtype, no 1p/19q co-deletion) but without typical MRI contrast enhancement.


Assuntos
Astrocitoma/diagnóstico por imagem , Astrocitoma/enzimologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/enzimologia , Isocitrato Desidrogenase/metabolismo , Tomografia por Emissão de Pósitrons , Tirosina/análogos & derivados , Idoso , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Humanos , Isocitrato Desidrogenase/genética , Imagem por Ressonância Magnética , Masculino
6.
Brain Tumor Pathol ; 36(4): 169-173, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31350684

RESUMO

Here, we report a rare case of anaplastic pleomorphic xanthoastrocytoma (PXA) associated with an H3G34 mutation. A 12-year-old male presented with loss of appetite, vomiting, headache, and a generalized seizure, and CT revealed a 9.0 cm left frontal lobe mass with some septal walls and a localized high-density area suggestive of hemorrhage or calcification, causing severe midline shift. He emergently underwent subtotal resection and the tumor was morphologically diagnosed as anaplastic PXA. DNA sequencing identified an H3F3A G34R mutation and a TP53 R273H mutation, and immunohistochemically, ATRX nuclear expression was lost. In CNS tumors, H3G34 mutations are essentially detected in glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors. Those tumors most likely comprise a single biological entity (high-grade glioma with H3G34 mutation) because of no significant difference in molecular profiling and prognosis between GBM and PNET morphologies. To our knowledge, our present case is the first one of anaplastic PXA associated with an H3G34 mutation, and whether it biologically corresponds to "high-grade glioma with H3G34 mutation" needs further studies.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Criança , Glioblastoma/genética , Glioma/genética , Humanos , Masculino , Mutação , Prognóstico
7.
Medicina (Kaunas) ; 55(8)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31357616

RESUMO

Being the fourth leading cause of cancer-related death, glial tumors are highly diverse tumor entities characterized by important heterogeneity regarding tumor malignancy and prognosis. However, despite the identification of important alterations in the genome of the glial tumors, there remains a gap in understanding the mechanisms involved in glioma malignancy. Previous research focused on decoding the genomic alterations in these tumors, but due to intricate cellular mechanisms, the genomic findings do not correlate with the functional proteins expressed at the cellular level. The development of mass spectrometry (MS) based proteomics allowed researchers to study proteins expressed at the cellular level or in serum that may provide new insights on the proteins involved in the proliferation, invasiveness, metastasis and resistance to therapy in glial tumors. The integration of data provided by genomic and proteomic approaches into clinical practice could allow for the identification of new predictive, diagnostic and prognostic biomarkers that will improve the clinical management of patients with glial tumors. This paper aims to provide an updated review of the recent proteomic findings, possible clinical applications, and future research perspectives in diffuse astrocytic and oligodendroglial tumors, pilocytic astrocytomas, and ependymomas.


Assuntos
Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Glioma/classificação , Glioma/genética , Proteômica/métodos , Astrocitoma/genética , Biomarcadores Tumorais/classificação , Humanos , Espectrometria de Massas/métodos , Estadiamento de Neoplasias/métodos , Neoplasias , Oligodendroglioma/genética , Prognóstico , Proteômica/instrumentação
8.
PLoS One ; 14(7): e0220146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31329636

RESUMO

Microvascular proliferation (MVP), an aberrant vascular structure containing multilayered mitotically active endothelial- and smooth-muscle cells/pericytes, is a histopathological hallmark of glioblastoma multiforme (GBM). Although MVP tends to be associated with high-grade glioma, it has also been detected in WHO grade I pilocytic astrocytoma (PA). However, little is known about the mechanism underlying its formation. Using TP53 point mutations as a marker for tumor-derived cells, we earlier reported that MVP was partially converted from tumor cells via mesenchymal transition. In the current study we used the KIAA1549-BRAF fusion gene as a marker to assess whether MVPs in PA contained tumor-derived cells and/or phenotypically distinct tumor cells expressing vascular markers. cDNA synthesized from frozen tissue of six PA patients operated at our institute was analyzed to detect the KIAA1549-BRAF fusion gene by reverse transcription polymerase chain reaction (RT-PCR) assay. The breakpoint in the fusion gene was identified by long and accurate PCR (LA-PCR) and Sanger sequencing of genomic DNA. Distinct tumor cells and cellular components of MVP were obtained by laser microdissection. For the qualitative and quantitative detection of the KIAA1549-BRAF fusion gene we performed genomic and digital PCR assays. Fluorescence in situ hybridization (FISH) was used to assess gene fusion in cellular components of MVP. Samples from three PA patients harbored the KIAA1549 exon 15, BRAF exon 9 fusion gene. In two patient samples with abundant MVP, RT-PCR assay detected strong bands arising from the KIAA1549-BRAF fusion gene in both tumor cells and cellular components of MVP. Digital PCR showed that vis-à-vis tumor tissue, its relative expression in cellular components of MVP was 42% in one- and 76% in another sample. FISH revealed amplified signals in both tumor cells and cellular components of MVP indicative of tandem duplication. Our findings suggest that in patients with PA, some cellular components of MVP contained tumor derived cell and/or phenotypically distinct tumor cells expressing vascular markers.


Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Microvasos/metabolismo , Proteínas de Fusão Oncogênica/genética , Adolescente , Adulto , Astrocitoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Microvasos/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Proteínas de Fusão Oncogênica/metabolismo
9.
J Neurooncol ; 144(1): 137-146, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31214915

RESUMO

INTRODUCTION: Epithelioid glioblastoma (EGBM) and anaplastic pleomorphic xanthoastrocytoma (APXA) are two rare entities with different prognoses. However, they share certain morphological and molecular features. MATERIALS AND METHODS: To better recognize EGBM and APXA and identify the prognostic factors associated with these tumors, EZH2 status, BRAF V600E mutations, and CDKN2A/B deletions were assessed in 15 APXA and 13 EGBM cases. RESULTS: The expression level of EZH2 was found to increase with tumor grade. Overexpression of EZH2 occurred in 69.2% (9/13) of EGBM cases and 20% (3/15) of APXA cases. In addition, 72.7% (8/11) of EGBM and 12.5% (1/8) of APXA cases harbored a CDKN2A homozygous deletion based on fluorescence in situ hybridization. BRAF V600E mutations were detected in 80% (8/10) of EGBM cases and 42.9% (3/7) of APXA cases. Furthermore, EGBM, which exhibited co-existing low-grade glioma-like lesions, was found to have strong EZH2 expression and high Ki-67 indexes only in epithelioid cells and not in low grade lesions. Univariate analysis demonstrated that abundant epithelioid cells, extensive necrosis, EZH2 overexpression and BRAF V600E mutations were significantly associated with decreased overall survival in EGBM and APXA patients (P < 0.05). CONCLUSIONS: The results suggested that testing for EZH2 expression and BRAF V600E mutations might be helpful to evaluate the prognoses of EGBM and APXA patients. The presence of heterogeneous EZH2 expression in biphasic EGBMs could also contribute to malignant progression.


Assuntos
Astrocitoma/patologia , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Deleção de Genes , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Astrocitoma/classificação , Astrocitoma/genética , Astrocitoma/metabolismo , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Células Epitelioides/metabolismo , Células Epitelioides/patologia , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
10.
Pathol Int ; 69(6): 372-377, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31218776

RESUMO

Glioneuronal tumor (GNT) is a rare central nervous system neoplasm composed of glial and neuronal components. Making the specific diagnosis of GNT can be challenging due to histopathological and genetical similarities among some GNTs and low-grade gliomas. We report a case of GNT with rosette-forming glioneuronal tumor, dysembryoplastic neuroepithelial tumor, and pilocytic astrocytoma-like morphology harboring FGFR1 mutation. A 16-year-old female presented with absence seizures. Magnetic resonance imaging revealed a right temporal lobe mass with multinodular enhancement by gadolinium administration. The tumor was mostly composed of oligodendrocyte-like cells (OLCs) with variable perinuclear haloes. Abundant Rosenthal fibers and eosinophilic granular bodies were identified. Neither mitotic figures nor areas of necrosis were seen. Focal neurocytic rosette features, involving ring-like arrays of OLCs around eosinophilic cores, were observed. Direct sequencing showed a missense mutation in FGFR1 K656E, whereas FGFR1 N546K, PIK3CA, and BRAF V600E were intact. KIAA1549-BRAF fusion was not detected by fluorescence in situ hybridization analysis.


Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Epilepsia/patologia , Glioma/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Astrocitoma/complicações , Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Epilepsia/diagnóstico , Epilepsia/etiologia , Feminino , Glioma/complicações , Glioma/diagnóstico , Glioma/genética , Humanos , Mutação/genética
11.
J Clin Neurosci ; 66: 231-234, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147230

RESUMO

Ganglioglioma (GG) is a mixed glio-neuronal tumour, comprised of a neoplastic glial component and dysplastic ganglion cells. GG is a tumour of unclear histogenesis; previous studies examining BRAF mutations and chromosome imprinting has provided evidence that both the neuronal and glial components likely arise from a common precursor. Both p.V600E mutation and KIAA1549-BRAF fusion have been described in pilocytic astrocytoma (PA) and GG, but they differ with regards to the rates of different BRAF alterations, and careful histological examination is an important component of patho-molecular correlations. More recently, cases of PA with gangliocytic differentiation (PA-GD) have been described, and these cases are thus far restricted to those with the KIAA1549-BRAF fusion. Here, we describe three cases of GGs in patients with history of previously diagnosed PAs. The cases differ with respect to the chronologic intervals between the PA and the GG diagnoses. In two of the cases, where the PA-GG diagnostic intervals are less than ten years, pathological review revealed the older specimens to have been misdiagnosed as PAs. In the third case, where the interval spanned multiple decades, the GG was found to be positive for both BRAF p.V600E immunohistochemistry (IHC) and for the KIAA1549-BRAF fusion. Molecular study for the BRAF p.V600E mutation was negative, proving the IHC result to be a false-positive. Our case demonstrates that cases of GG can harbour the KIAA1549-BRAF fusion, even with positive BRAF p.V600E IHC results, and the case highlights a diagnostic challenge that may be encountered.


Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Erros de Diagnóstico , Progressão da Doença , Ganglioglioma/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Astrocitoma/genética , Neoplasias Encefálicas/genética , Feminino , Ganglioglioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética
12.
J Clin Neurosci ; 66: 196-201, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147232

RESUMO

Alterations in the BRAF gene have been reported to play a key role in the tumorigenesis of various tumors. Recent studies have shown the existence of BRAF alterations in ganglioglioma (GG), pilocytic astrocytoma (PA), pleomorphic xanthoastrocytomas (PXA), and epithelioid glioblastoma (eGBM). The focus of this review was the association between the clinical characteristics and BRAF status in these glial and glioneuronal tumors. The BRAF abnormalities, KIAA1549-BRAF fusion and BRAF mutation, were detected in approximately 50% of the analyzed tumors regardless of the tumor location, and there were site-specific BRAF abnormalities that became more remarkable on analysis by each tumor subtype. The median age of patients with KIAA1549-BRAF fusion was much lesser than that of those with BRAF mutations. Histological analysis indicates that the existence of KIAA1549-BRAF fusion is related to pilocytic morphology. The review of imaging features indicated that cyst formation is associated with the existence of KIAA1549-BRAF fusion in PA and GG and the lack of BRAF mutation in GG. Hemorrhage was significantly present in cases of GG with KIAA1549-BRAF fusion, but no relevance was shown in cases with BRAF mutations. No significant relevance was detected between the presence of calcification and BRAF alterations. Our clinical and genetic review of BRAF-related tumors indicated that the KIAA1549-BRAF fusion was strongly associated with PA, but not with other glial and glioneuronal tumors.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Ganglioglioma/genética , Glioblastoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Ganglioglioma/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Humanos , Mutação/genética , Neuroglia/patologia
13.
BMC Cancer ; 19(1): 544, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170943

RESUMO

BACKGROUND: The understanding of the molecular biology of pediatric neuronal and mixed neuronal-glial brain tumors is still insufficient due to low frequency and heterogeneity of those lesions which comprise several subtypes presenting neuronal and/or neuronal-glial differentiation. Important is that the most frequent ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNET) showed limited number of detectable molecular alterations. In such cases analyses of additional genomic mechanisms seem to be the most promising. The aim of the study was to evaluate microRNA (miRNA) profiles in GGs, DNETs and pilocytic asytrocytomas (PA) and test the hypothesis of plausible miRNA connection with histopathological subtypes of particular pediatric glial and mixed glioneronal tumors. METHODS: The study was designed as the two-stage analysis. Microarray testing was performed with the use of the miRCURY LNA microRNA Array technology in 51 cases. Validation set comprised 107 samples used during confirmation of the profiling results by qPCR bioinformatic analysis. RESULTS: Microarray data was compared between the groups using an analysis of variance with the Benjamini-Hochberg procedure used to estimate false discovery rates. After filtration 782 miRNAs were eligible for further analysis. Based on the results of 10 × 10-fold cross-validation J48 algorithm was identified as the most resilient to overfitting. Pairwise comparison showed the DNETs to be the most divergent with the largest number of miRNAs differing from either of the two comparative groups. Validation of array analysis was performed for miRNAs used in the classification model: miR-155-5p, miR-4754, miR-4530, miR-628-3p, let-7b-3p, miR-4758-3p, miRPlus-A1086 and miR-891a-5p. Model developed on their expression measured by qPCR showed weighted AUC of 0.97 (95% CI for all classes ranging from 0.91 to 1.00). A computational analysis was used to identify mRNA targets for final set of selected miRNAs using miRWalk database. Among genomic targets of selected molecules ZBTB20, LCOR, PFKFB2, SYNJ2BP and TPD52 genes were noted. CONCLUSIONS: Our data showed the existence of miRNAs which expression is specific for different histological types of tumors. miRNA expression analysis may be useful in in-depth molecular diagnostic process of the tumors and could elucidate their origins and molecular background.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Árvores de Decisões , Ganglioglioma/genética , MicroRNAs/genética , Transcriptoma , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Análise em Microsséries , Estudos Prospectivos , Curva ROC
14.
Neuroradiology ; 61(9): 1023-1031, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31134296

RESUMO

PURPOSE: There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features. METHODS: Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis. RESULTS: There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393). CONCLUSIONS: Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.


Assuntos
Astrocitoma/diagnóstico por imagem , Astrocitoma/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA/genética , Isocitrato Desidrogenase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/mortalidade , Neoplasias Encefálicas/mortalidade , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Adulto Jovem
15.
Anticancer Res ; 39(5): 2299-2306, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092421

RESUMO

BACKGROUND/AIM: Death receptor 6 (DR6) is a member of the tumor necrosis factor receptor superfamily. The expression of DR6 is elevated in different kinds of tumors including ovarian, breast cancer and adult sarcoma. In these tumors, the receptor may be handled as a new diagnostic and prognostic marker. Thus, we investigated the expression of DR6 in gliomas. MATERIALS AND METHODS: Tumor and control tissues were extracted during neurosurgery and grouped according to the WHO classification. DR6 expression was investigated in low- and high-grade gliomas PCR (n=70), immunofluorescence staining (n=33) and western blot (n=58). Additional analysis of TCGA-data was performed to assess the general alteration of DR6 in cancer and influence of IDH-mutation on DR6 expression in gliomas. RESULTS: The expression of DR6 was significantly enhanced in gliomas (p<0.05). It showed a trend towards rising expression with increasing malignancy of the tumor. Chemotherapy treatment could have an influence on DR6 expression. CONCLUSION: In our investigation, DR6 acts as a potential suitable diagnostic marker for gliomas.


Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/genética , Glioma/genética , Receptores do Fator de Necrose Tumoral/genética , Astrocitoma/tratamento farmacológico , Astrocitoma/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Mutação , Gradação de Tumores
16.
BMC Cancer ; 19(1): 473, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109310

RESUMO

BACKGROUND: There are limited effective drugs that can reach the brain to target brain tumors, in particular glioblastoma, which is one of the most difficult cancers to be cured from. Because the overexpression of the sigma-2 receptor is frequently reported in glioma clinical samples and associated with poor prognosis and malignancy, we herein studied the anti-tumor effect of the sigma-2 receptor agonist PB221 (4-cyclohexyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperidine) on an anaplastic astrocytoma tumor model based on previous encouraging results in pancreatic cancer and neuroblastoma SK-N-SH cells. METHODS: The expression of the sigma-2 receptor, transmembrane protein 97 (TMEM97), in ALTS1C1 and UN-KC6141 cell lines was measured by RT-PCR and quantitative RT-PCR. The binding of sigma-2 receptor fluorescent ligands PB385 (6-[5-[3-(4-cyclohexylpiperazin-1-yl)propyl]-5,6,7,8-tetrahydronaphthalen-5-yloxy]-N-(7-nitro-2,1,3-benzoxadiazol-4-yl)hexanamine) and NO1 (2-{6-[2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one-5-yloxy]hexyl}-5-(dimethylamino)isoindoline-1,3-dione) was examined by flow cytometry and the fluorescent plate reader. The antitumor activity of PB221 was initially examined in the murine brain tumor cell line ALTS1C1 and then in the murine pancreatic cell line UN-KC6141. The potential therapeutic efficacy of PB221 for murine brain tumors was examined by in vitro migration and invasion assays and in vivo ectopic and orthotopic ALTS1C1 tumor models. RESULTS: The IC50 of PB221 for ALTS1C1 and UN-KC6141 cell lines was 10.61 ± 0.96 and 13.13 ± 1.15 µM, respectively. A low dose of PB221 (1 µM) significantly repressed the migration and invasion of ALTS1C1 cells, and a high dose of PB221 (20 µM) resulted in the apoptotic cell death of ALTS1C1 cells. These effects were reduced by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine, suggesting mitochondrial oxidative stress is involved. The in vivo study revealed that PB221 effectively retarded tumor growth to 36% of the control tumor volume in the ectopic intramuscular tumor model and increased the overall survival time by 20% (from 26 to 31 days) in the orthotopic intracerebral tumor model. CONCLUSIONS: This study demonstrates that the sigma-2 receptor agonist PB221 has the potential to be an alternative chemotherapeutic drug for brain tumors with comparable side effects as the current standard-of-care drug, temozolomide.


Assuntos
Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Proteínas de Membrana/genética , Piperidinas/administração & dosagem , Tetra-Hidronaftalenos/administração & dosagem , Animais , Astrocitoma/genética , Astrocitoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Proteínas de Membrana/agonistas , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Tetra-Hidronaftalenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Brain Tumor Pathol ; 36(2): 52-55, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30945015

RESUMO

Pilomyxoid astrocytoma is a variant of pilocytic astrocytoma and the clinical, histological and molecular data point to a very close relationship as well as a more aggressive biological behavior for the former. WHO 2016 classification does not provide a specific grade for these neoplasms, but there is sufficient evidence in the literature that pilomyxoid astrocytoma has slightly worse prognosis than typical pilocytic astrocytoma. There is increasing evidence that in addition to the MAPK pathway alterations, pilomyxoid astrocytomas harbor genetic alterations that distinguish them from typical pilocytic astrocytoma.


Assuntos
Astrocitoma/metabolismo , Astrocitoma/patologia , Astrocitoma/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/fisiologia
18.
Brain Tumor Pathol ; 36(2): 74-83, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30929113

RESUMO

Pediatric low-grade gliomas (PLGGs) have relatively favorable prognosis and some resectable PLGGs, such as cerebellar pilocytic astrocytoma, can be cured by surgery alone. However, many PLGG cases are unresectable and some of them undergo tumor progression. Therefore, a multidisciplinary approach is necessary to treat PLGG patients. Recent genomic analysis revealed a broad genomic landscape underlying PLGG. Notably, the majority of PLGGs present MAPK pathway-associated genomic alterations and MAPK signaling-dependent tumor progression. Following preclinical evidence, many clinical trials based on molecular target therapy have been conducted on PLGG patients, some of whom exhibited durable response to target therapy. Here, we provide an overview of PLGG genetics and the evidence supporting the application of molecular target therapy in these patients.


Assuntos
Glioma/genética , Glioma/patologia , Adolescente , Astrocitoma/genética , Astrocitoma/patologia , Astrocitoma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Glioma/terapia , Humanos , Lactente , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas B-raf
19.
Br J Neurosurg ; 33(5): 536-540, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31018710

RESUMO

Purpose: The 2016 WHO tumour classification highlights the role of IDH1/2 gene mutation and 1p/19q co-deletion in classifying grade II/III gliomas. A recent cIMPACT-NOW update proposes the use of the term 'Not Elsewhere Classified' (NEC) for IDH-mutant, non co-deleted tumours. Here we show how the incorporation of ATRX immunohistochemistry can be used to better delineate the NEC group. Methods: Clinical data was collected for 112 patients (59% male) treated at our unit. Mutations in IDH1/2 genes were detected by pyrosequencing or immunohistochemistry, 1p/19q co-deletion was assessed with fluorescence in situ hybridisation and ATRX status was determined using immunohistochemical techniques. Tumours were grouped on the basis of molecular markers and outcomes compared. Results: The mean age of diagnosis was 42.6 years (20-73 years). There were 88 oligodendrogliomas (II = 47, III = 41), 18 diffuse astrocytomas (II = 9, III = 9) and 6 oligoastrocytomas (II = 4, III = 2). The majority of gliomas (87.5%) had mutations in IDH1/2. 1p/19q co-deletion was significantly associated with oligodendroglial morphology (p = < 0.001) and was mutually exclusive with ATRX mutation. Classification on the basis of molecular information showed a significant different in survival between the groups. Conclusions: ATRX immunohistochemisty is a useful adjunct which can be used with IDH mutation status, 1p/19q co-deletion and histological findings to further define tumour groups. More work is needed to understand the molecular profiles and prognostic implications for non co-deletion, ATRX preserved cases.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Mutação/genética , Oligodendroglioma/genética , Proteína Nuclear Ligada ao X/genética , Adulto , Idoso , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Feminino , Humanos , Imuno-Histoquímica , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/patologia , Prognóstico , Adulto Jovem
20.
J Neurooncol ; 143(2): 187-196, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004262

RESUMO

INTRODUCTION: Tumour-associated angiogenesis is associated with the malignancy and poor prognosis of glioma. Isocitrate dehydrogenase (IDH) mutations are present in the majority of lower-grade (WHO grade II and III) and secondary glioblastomas, but their roles in tumour angiogenesis remain unclear. METHODS: Using magnetic resonance imaging (MRI), the cerebral blood flow (CBF) of IDH-mutated glioma was measured and compared with the IDH-wildtype glioma. The densities of microvessels in IDH-mutated and wildtype astrocytoma and glioblastoma were assessed by immunohistochemical (IHC) staining with CD34, and the pericytes were labelled with α-smooth muscle antigen (α-SMA), neural-glial antigen 2 (NG2) and PDGF receptor-ß (PDGFR-ß), respectively. Furthermore, glia-specific mutant IDH1 knock-in mice were generated to evaluate the roles of mutant IDH1 on brain vascular architectures. The transcriptions of the angiogenesis-related genes were assessed in TCGA datasets, including ANGPT1, PDGFB and VEGFA. The expressions of these genes were further determined by western blot in U87-MG cells expressing a mutant IDH1 or treated with 2-HG. RESULTS: The MRI results indicated that CBF was reduced in the IDH-mutated gliomas. The IHC staining showed that the pericyte coverages of microvessels were significantly decreased, but the microvessel densities (MVDs) were only slightly decreased in IDH-mutated glioma. The mutant IDH1 knock-in also impeded the pericyte coverage of brain microvessels in mice. Moreover, the TCGA database showed the mRNA levels of angiogenesis factors, including ANGPT1, PDGFB and VEGFA, were downregulated, and their promoters were also highly hyper-methylated in IDH-mutated gliomas. In addition, both mutant IDH1 and D-2-HG could downregulate the expression of these genes in U87-MG cells. CONCLUSIONS: Our results suggested that IDH mutations could reduce the pericyte coverage of microvessels in astrocytic tumours by inhibiting the expression of angiogenesis factors. As vascular pericytes play an essential role in maintaining functional blood vessels to support tumour growth, our findings imply a potential avenue of therapeutic strategy for IDH-mutated gliomas.


Assuntos
Astrocitoma/patologia , Isocitrato Desidrogenase/genética , Microvasos/patologia , Mutação , Neovascularização Patológica , Pericitos/patologia , Animais , Astrocitoma/genética , Astrocitoma/metabolismo , Circulação Cerebrovascular , Humanos , Isocitrato Desidrogenase/fisiologia , Camundongos , Microvasos/metabolismo , Pericitos/metabolismo , Células Tumorais Cultivadas
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