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1.
Acta Neuropathol ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31781912

RESUMO

Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.

2.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

3.
Acta Neuropathol ; 134(3): 507-516, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28401334

RESUMO

Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes 'pedGBM_MYCN' (enriched for MYCN amplification), 'pedGBM_RTK1' (enriched for PDGFRA amplification) and 'pedGBM_RTK2' (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Histonas/genética , Isocitrato Desidrogenase/genética , Mutação , Adolescente , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Criança , Pré-Escolar , Metilação de DNA , Análise Mutacional de DNA , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Histonas/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Prognóstico , Regiões Promotoras Genéticas
4.
Genes Chromosomes Cancer ; 55(5): 418-27, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26841698

RESUMO

Intraocular medulloepithelioma (IO-MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. Little is known about the cytogenetics, molecular biology, and pathogenesis of this tumor. In the present study we investigated the mutational landscape of 19 IO-MEPL using targeted next-generation sequencing. Routinely prepared paraffin-embedded samples were assessed with high-coverage genome sequencing on the Illumina NextSeq 500 platform using a customized gene panel set covering the coding region of 130 genes. This revealed several notable genomic alterations, including mutations of DICER1 (6 tumors) and KMT2D (also known as MLL2; 5 tumors)-which are frequently recurrent and mutually exclusive molecular events for IO-MEPL. Non-recurrent mutations in the cancer-associated genes BRCA2, BRCA1, NOTCH2, CDH1, and GSE1 were also identified. IO-MEPL samples harboring a DICER1 mutation disclosed few chromosomal alterations and formed a separate DNA methylation cluster, indicating potential differences in genetic and epigenetic events arising perhaps from the presence of this aberration in the tumor genome. The high proportion of recurrent somatic DICER1 and KMT2D mutations in this series of sporadic IO-MEPL points to their likely important roles in the molecular pathogenesis of these rare embryonal tumors, and perhaps suggests the existence of distinct molecular variants of IO-MEPL. Although the precise role of these recurrent mutations in the development of IO-MEPL, and their relationship to pro-oncogenic molecular mechanisms, have yet to be determined, unraveling their roles could eventually be exploited for nonsurgical therapies of these neoplasms.


Assuntos
RNA Helicases DEAD-box/genética , Proteínas de Ligação a DNA/genética , Neoplasias Oculares/genética , Mutação , Proteínas de Neoplasias/genética , Tumores Neuroectodérmicos Primitivos/genética , Ribonuclease III/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade
5.
Acta Neuropathol ; 131(1): 137-46, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26482474

RESUMO

In contrast to the relative morphological uniformity of histone H3 K27-mutant high-grade gliomas, H3 G34-mutant tumors present as a histopathologically heterogeneous group of neoplasms, with microscopic characteristics typical of either glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors (CNS-PNET). In the current study, we performed an integrative clinical, histopathological and molecular analysis of 81 G34-mutant CNS tumors. Routinely prepared tumor tissues were investigated for genomic and epigenomic alterations. Despite their divergent histopathological appearance, CNS tumors with H3.3 G34 mutations displayed uniform epigenetic signatures, suggesting a single biological origin. Comparative cytogenetic analysis with other GBM subtypes disclosed a high frequency and high specificity of 3q and 4q loss across G34-mutant tumors. PDGFRA amplification was more common in cases with GBM than with PNET morphology (36 vs. 5 %, respectively), while CCND2 amplifications showed the opposite trend (5 vs. 27 %). Survival analysis revealed the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively. No difference in outcome was found between morphological variants (GBM vs. PNET). Thus, different histological variants of G34-mutant CNS tumors likely comprise a single biological entity (high-grade glioma with H3 G34 mutation, HGG_G34), which should be outlined in future diagnostic and therapeutic classifications. Screening for H3.3 G34 mutation should therefore be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum.


Assuntos
Glioblastoma/genética , Glioma/genética , Histonas/genética , Mutação/genética , Neoplasias Supratentoriais/genética , Adolescente , Adulto , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Criança , Epigenômica/métodos , Feminino , Glioblastoma/diagnóstico , Glioma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Supratentoriais/diagnóstico , Adulto Jovem
6.
Acta Neuropathol ; 128(2): 279-89, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24337497

RESUMO

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Tumores Neuroectodérmicos Primitivos/metabolismo , Tumores Neuroectodérmicos Primitivos/patologia , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 19 , Variações do Número de Cópias de DNA , Metilação de DNA , Diagnóstico Diferencial , Feminino , Loci Gênicos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lactente , Masculino , Recidiva Local de Neoplasia , Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Embrionárias de Células Germinativas/genética , Tumores Neuroectodérmicos Primitivos/classificação , Tumores Neuroectodérmicos Primitivos/genética , Análise de Sobrevida
7.
Lancet Oncol ; 14(12): 1200-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24140199

RESUMO

BACKGROUND: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. METHODS: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. RESULTS: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). INTERPRETATION: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Meduloblastoma/genética , Meduloblastoma/secundário , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Adolescente , Canadá , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/terapia , Criança , Pré-Escolar , Europa (Continente) , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Meduloblastoma/classificação , Meduloblastoma/mortalidade , Meduloblastoma/terapia , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Fenótipo , Análise de Componente Principal , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Estados Unidos
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