RESUMEN
Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.
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Neoplasias Cerebelosas/genética , Meduloblastoma/genética , Adolescente , Adulto , Biomarcadores de Tumor/genética , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Estudios de Cohortes , Femenino , Humanos , Masculino , Meduloblastoma/mortalidad , Meduloblastoma/patología , Supervivencia sin Progresión , Factores de Riesgo , Adulto JovenRESUMEN
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.
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Biomarcadores de Tumor/metabolismo , Neoplasias Cerebelosas/genética , Meduloblastoma/genética , Neurocalcina/metabolismo , Adolescente , Neoplasias Cerebelosas/patología , Niño , Preescolar , Femenino , Perfilación de la Expresión Génica , Humanos , Lactante , Recién Nacido , Masculino , Meduloblastoma/patología , Pronóstico , TranscriptomaRESUMEN
Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) were outlined in the current WHO classification of tumors of the nervous system as two distinct histological MB variants. However, they are often considered as cognate SHH MB entities, and it is a reason why some clinical MB trials do not separate the patients with DNMB or MBEN histology. In the current study, we performed an integrated DNA/RNA-based molecular analysis of 83 DNMB and 36 MBEN to assess the etiopathogenetic relationship between these SHH MB variants. Methylation profiling revealed "infant" and "children" SHH MB clusters but neither DNMB nor MBEN composed separate epigenetic cohorts, and their profiles were intermixed within the "infant" cluster. In contrast, RNA-based transcriptional profiling disclosed that expression signatures of all MBEN were clustered separately from most of DNMB and a set of differentially expressed genes was identified. MBEN transcriptomes were enriched with genes associated with synaptic transmission, neuronal differentiation and metabolism, whereas DNMB profiling signatures included sets of genes involved in phototransduction and NOTCH signaling pathways. Thus, DNMB and MBEN are distinct tumor entities within the SHH MB family whose biology is determined by different transcriptional programs. Therefore, we recommend a transcriptome analysis as an optimal molecular tool to discriminate between DNMB and MBEN, which may be of benefit for patients' risk stratification in clinical trials. Molecular events identified in DNMB by RNA sequencing could be considered in the future as potent molecular targets for novel therapeutic interventions in treatment-resistant cases.
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Neoplasias Cerebelosas/genética , Metilación de ADN , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Meduloblastoma/genética , Transcripción Genética , Adolescente , Edad de Inicio , Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Niño , Preescolar , Islas de CpG , ADN de Neoplasias/química , Supervivencia sin Enfermedad , Femenino , Fusión Génica , Proteínas Hedgehog/fisiología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Meduloblastoma/clasificación , Meduloblastoma/mortalidad , Meduloblastoma/patología , Mutación , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/genética , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , ARN Mensajero/biosíntesis , ARN Neoplásico/genética , Transducción de Señal , TranscriptomaRESUMEN
Medulloblastoma with extensive nodularity (MBEN) is a rare histological variant of medulloblastoma (MB). These tumors are usually occurring in the first 3 years of life and are associated with good prognosis. Molecular analyses of MBEN, mostly limited to single cases or small series, have shown that they always classify as sonic hedgehog (SHH)-driven MB. Here, we have analyzed 25 MBEN through genome-wide DNA methylation, copy-number profiling and targeted next-generation sequencing. Results of these analyses were compared with molecular profiles of other SHH MB histological variants. As expected, the vast majority of MBEN (23/25) disclosed SHH-associated epigenetic signatures and mutational landscapes but, surprisingly, two MBEN were classified as Group 3/4 MB. Most MBEN classified as SHH MB displayed SHH-related and mutually exclusive mutations in either SUFU, or PTCH1, or SMO at similar frequencies. However, only SUFU mutations were also identified in the germ-line. Most of SUFU-associated MBEN eventually recurred but patients were treated successfully with second-line high-dose chemotherapy. Altogether, our data show that risk stratification even for well-recognizable histologies such as MBEN cannot rely on histology alone but should include additional molecular analyses such as methylation profiling and DNA sequencing. For all patients with "MBEN" histology, we recommend sequencing SUFU and PTCH1 in the tumor as well as in the germ-line for further clinical stratification and choice of the optimal treatment strategy upfront.
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Neoplasias Cerebelosas/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , Proteínas Represoras/genética , Adolescente , Supervivientes de Cáncer , Neoplasias Cerebelosas/patología , Niño , Preescolar , Estudios de Cohortes , Metilación de ADN/genética , Femenino , Humanos , Masculino , Meduloblastoma/patología , Fosfopiruvato Hidratasa/metabolismo , Análisis de Supervivencia , Adulto JovenRESUMEN
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.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , Histonas/genética , Isocitrato Deshidrogenasa/genética , Mutación , Adolescente , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Carcinogénesis/genética , Niño , Preescolar , Metilación de ADN , Análisis Mutacional de ADN , Femenino , Glioblastoma/metabolismo , Glioblastoma/patología , Histonas/metabolismo , Humanos , Isocitrato Deshidrogenasa/metabolismo , Masculino , Pronóstico , Regiones Promotoras GenéticasRESUMEN
Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.
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Neoplasias del Tronco Encefálico/diagnóstico por imagen , Glioma/diagnóstico por imagen , Servicios de Información , Cooperación Internacional , Imagen por Resonancia Magnética , Sistema de Registros , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Puente/diagnóstico por imagen , Adulto JovenRESUMEN
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.
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ARN Helicasas DEAD-box/genética , Proteínas de Unión al ADN/genética , Neoplasias del Ojo/genética , Mutación , Proteínas de Neoplasias/genética , Tumores Neuroectodérmicos Primitivos/genética , Ribonucleasa III/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana EdadRESUMEN
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.
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Glioblastoma/genética , Glioma/genética , Histonas/genética , Mutación/genética , Neoplasias Supratentoriales/genética , Adolescente , Adulto , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Niño , Epigenómica/métodos , Femenino , Glioblastoma/diagnóstico , Glioma/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Supratentoriales/diagnóstico , Adulto JovenRESUMEN
Pediatric glioblastoma (pedGBM) is amongst the most common malignant brain tumors of childhood and carries a dismal prognosis. In contrast to adult GBM, few molecular prognostic markers for the pediatric counterpart have been established. We, therefore, investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1-18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations via direct sequencing or FISH. Unexpectedly, a subset of histologically diagnosed GBM (n = 40, 20 %) displayed methylation profiles similar to those of either low-grade gliomas or pleomorphic xanthoastrocytomas (PXA). These tumors showed a markedly better prognosis, with molecularly PXA-like tumors frequently harboring BRAF V600E mutations and 9p21 (CDKN2A) homozygous deletion. The remaining 162 tumors with pedGBM molecular signatures comprised four subgroups: H3.3 G34-mutant (15 %), H3.3/H3.1 K27-mutant (43 %), IDH1-mutant (6 %), and H3/IDH wild-type (wt) GBM (36 %). These subgroups were associated with specific cytogenetic aberrations, MGMT methylation patterns and clinical outcomes. Analysis of follow-up data identified a set of biomarkers feasible for use in risk stratification: pedGBM with any oncogene amplification and/or K27M mutation (n = 124) represents a particularly unfavorable group, with 3-year overall survival (OS) of 5 %, whereas tumors without these markers (n = 38) define a more favorable group (3-year OS ~70 %).Combined with the lower grade-like lesions, almost 40 % of pedGBM cases had distinct molecular features associated with a more favorable outcome. This refined prognostication method for pedGBM using a molecular risk algorithm may allow for improved therapeutic choices and better planning of clinical trial stratification for this otherwise devastating disease.
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Biomarcadores de Tumor/genética , Genes p16 , Glioblastoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Astrocitoma/genética , Neoplasias Encefálicas/genética , Transformación Celular Neoplásica/genética , Niño , Preescolar , Metilación de ADN , Epigenómica , Femenino , Genómica , Glioblastoma/patología , Glioblastoma/fisiopatología , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Mutación , Clasificación del Tumor/métodos , Pronóstico , Análisis de Secuencia de ADNRESUMEN
Intraocular medulloepithelioma (IO MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. These ocular neoplasms have been compared with intracranial medulloepitheliomas or other histologic variants of CNS embryonal tumor with multilayered rosettes (CNS ETMR) due to their morphological mimicry. We performed comprehensive molecular analysis to explore the histogenetic and biologic relationships between 22 IO MEPL and 68 CNS ETMR. Routinely prepared paraffin-embedded samples were assessed for genome-wide methylation profiles using the Illumina Methylation 450k BeadChip array. We identified strong cytogenetic and epigenetic differences between ocular neoplasms and CNS ETMR. None of the IO MEPL cases displayed the ETMR-specific amplification of the C19MC locus. Instead, cytogenetic analysis of the IO MEPL showed numerous copy number aberrations which involved either whole chromosomes or chromosomal arms; recurrent aberrations in these tumors affected chromosomes 1p, 4, 8 and 16p. DNA methylation patterns were also strikingly different between these two tumor entities, suggesting that they do not share common origins and biological behaviors. Comparative cluster analysis of 198 pediatric CNS tumors and 22 IO MEPL revealed a clear demarcation of the CNS ETMR and IO MEPL profiles from other CNS entities. In conclusion, although IO MEPL shares some histopathological features with CNS ETMR, they manifest striking molecular diversity at the cytogenetic and epigenetic levels. Consequently they deserve a separate nosologic designation in future tumor classifications, where CNS MEPL could be designated as a histological variant of CNS ETMR.
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Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Ojo/clasificación , Neoplasias de Células Germinales y Embrionarias/clasificación , Tumores Neuroectodérmicos Primitivos/clasificación , Adolescente , Adulto , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Análisis por Conglomerados , Neoplasias del Ojo/genética , Neoplasias del Ojo/patología , Femenino , Dosificación de Gen , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Estudios Retrospectivos , TranscriptomaAsunto(s)
Neoplasias Cerebelosas/genética , Proteínas Hedgehog/fisiología , Meduloblastoma/genética , Proteínas de Neoplasias/fisiología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/terapia , Niño , Preescolar , Terapia Combinada , Irradiación Craneana , ADN de Neoplasias/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Meduloblastoma/mortalidad , Meduloblastoma/patología , Meduloblastoma/terapia , Mutación , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Receptor Patched-1/genética , Receptor Patched-1/fisiología , Receptor Patched-2 , ARN Mensajero/genética , ARN Neoplásico/genética , Adulto JovenRESUMEN
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.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Tumores Neuroectodérmicos Primitivos/metabolismo , Tumores Neuroectodérmicos Primitivos/patología , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Niño , Preescolar , Cromosomas Humanos Par 19 , Variaciones en el Número de Copia de ADN , Metilación de ADN , Diagnóstico Diferencial , Femenino , Sitios Genéticos , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lactante , Masculino , Recurrencia Local de Neoplasia , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/genética , Tumores Neuroectodérmicos Primitivos/clasificación , Tumores Neuroectodérmicos Primitivos/genética , Análisis de SupervivenciaRESUMEN
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.
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Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Meduloblastoma/genética , Meduloblastoma/secundario , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Adolescente , Canadá , Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/terapia , Niño , Preescolar , Europa (Continente) , Femenino , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Meduloblastoma/clasificación , Meduloblastoma/mortalidad , Meduloblastoma/terapia , Recurrencia Local de Neoplasia/clasificación , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Fenotipo , Análisis de Componente Principal , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Estados UnidosRESUMEN
Central nervous system (CNS) tumors in children comprise a highly heterogenous and complex group of diseases. Historically, diagnosis and confirmation of these tumors were routinely based on histological examination. However, recently obtained data demonstrate that such a diagnostic approach is not completely accurate and could lead to misdiagnosis. Also, in recent times, the quantity and quality of molecular diagnostic methods have greatly improved, which influences the current classification methods and treatment approach for pediatric CNS tumors. Nowadays, molecular methods, such as DNA methylation profiling, are an integral part of diagnosing brain and spinal tumors in children. In this paper, we present the case of an infant with a posterior fossa tumor who demonstrated a non-specific morphology and whose diagnosis was verified only after DNA methylation.
RESUMEN
PURPOSE: International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing approximately 60% of tumors. However, very few clinical centers worldwide possess the technical capabilities to determine DNA methylation profiles or other molecular parameters of high risk for group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an IHC marker as a clinically tractable method for improved medulloblastoma risk stratification. EXPERIMENTAL DESIGN: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. RESULTS: TPD52 IHC positivity represented a significant independent predictor of early relapse and death for group 3/4 medulloblastoma [HRs between 3.67 and 26.7; 95% confidence interval (CI) between 1.00 and 706.23; P = 0.05, 0.017, and 0.0058]. Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing state-of-the-art risk stratification schemes, and reclassified approximately 50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity was a predictive indicator of poor response to chemotherapy [HR, 12.66; 95% CI, 3.53-45.40; P < 0.0001], suggesting important implication for therapeutic choices. CONCLUSIONS: This study redefines the approach to risk stratification in group 3/4 medulloblastoma in global practice. Because integration of TPD52 IHC in classification algorithms significantly improved outcome prediction, this test could be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
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Neoplasias Cerebelosas , Meduloblastoma , Biomarcadores de Tumor/genética , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/terapia , Humanos , Inmunohistoquímica , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Meduloblastoma/terapia , Proteínas de Neoplasias , Pronóstico , Factores de TranscripciónRESUMEN
BACKGROUND: Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology. Approximately 70% of adult MB disclose a sonic hedgehog (SHH) molecular signature in contrast to about 30% in pediatric cohorts. In addition, adult SHH-MB (aSHH-MB) are clinically heterogeneous but there is consensus neither on their optimal treatment nor on risk stratification. Thus, the identification of clinically relevant molecular subsets of aSHH-MB and identification of potential treatment targets remains inconclusive. METHODS: We analyzed 96 samples of institutionally diagnosed aSHH-MB through genome-wide DNA methylation profiling, targeted DNA sequencing, and RNA sequencing to identify molecular subcategories of these tumors and assess their prognostic significance. RESULTS: We defined two aSHH-MB numerically comparable epigenetic subsets with clinical and molecular variability. The subset "aSHH-MBI" (46%/48%) was associated with PTCH1/SMO (54%/46%) mutations, "neuronal" transcriptional signatures, and favorable outcomes after combined radio-chemotherapy (5-year PFS = 80% and OS = 92%). The clinically unfavorable "aSHH-MBII" subset (50%/52%; 5-year PFS = 24% and OS = 45%) disclosed GLI2 amplifications (8%), loss of 10q (22%), and gene expression signatures associated with angiogenesis and embryonal development. aSHH-MBII tumors revealed strong and ubiquitous expression of VEGFA both at transcript and protein levels that was correlated with unfavorable outcome. CONCLUSIONS: (1) The histologically uniform aSHH-MB cohort exhibits clear molecular heterogeneity separating these tumors into two molecular subsets (aSHH-MBI and aSHH-MBII), which are associated with different cytogenetics, mutational landscapes, gene expression signatures, and clinical course. (2) VEGFA appears to be a promising biomarker to predict clinical course, which needs further prospective validation as its potential role in the pathogenesis of this subset.
Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Adulto , Neoplasias Cerebelosas/genética , Niño , Proteínas Hedgehog/genética , Humanos , Meduloblastoma/genética , Pronóstico , Transcriptoma , Factor A de Crecimiento Endotelial VascularRESUMEN
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms posing diagnostic challenge due to a lack of defining molecular markers. CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL) emerged as a distinct pediatric brain tumor entity from a pool previously diagnosed as primitive neuroectodermal tumors of the central nervous system (CNS-PNETs). Current standard of identifying CNS_NBL relies on molecular analysis. We set out to establish immunohistochemical markers allowing safely distinguishing CNS_NBL from morphological mimics. To this aim we analyzed a series of 84 brain tumors institutionally diagnosed as CNS-PNET. As expected, epigenetic analysis revealed different methylation groups corresponding to the (1) CNS-NBL (24%), (2) glioblastoma IDH wild-type subclass H3.3 G34 (26%), (3) glioblastoma IDH wild-type subclass MYCN (21%) and (4) ependymoma with RELA_C11orf95 fusion (29%) entities. Transcriptome analysis of this series revealed a set of differentially expressed genes distinguishing CNS_NBL from its mimics. Based on RNA-sequencing data we established SOX10 and ANKRD55 expression as genes discriminating CNS_NBL from other tumors exhibiting CNS-PNET. Immunohistochemical detection of combined expression of SOX10 and ANKRD55 clearly identifies CNS_NBL discriminating them to other hemispheric CNS neoplasms harboring "PNET-like" microscopic appearance. Owing the rarity of CNS_NBL, a confirmation of the elaborated diagnostic IHC algorithm will be necessary in prospective patient series.
Asunto(s)
Biomarcadores de Tumor/genética , Proteínas Portadoras/genética , Neoplasias del Sistema Nervioso Central , Factores de Transcripción Forkhead/genética , Neuroblastoma , Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/genética , Factores de Transcripción SOXE/genética , Adolescente , Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Metilación de ADN/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/genética , Neuroblastoma/patología , Tumores Neuroectodérmicos Primitivos/clasificación , Tumores Neuroectodérmicos Primitivos/patologíaRESUMEN
BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.
Asunto(s)
Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Neoplasias de Células Germinales y Embrionarias , Tumores Neuroectodérmicos Primitivos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/terapia , Factores de Transcripción Forkhead , Humanos , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/terapia , Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/terapia , Patología Molecular , Estudios RetrospectivosRESUMEN
PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Cerebelosas/genética , Metilación de ADN , Meduloblastoma/genética , Recurrencia Local de Neoplasia , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/terapia , Niño , Preescolar , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Epigenoma , Epigenómica , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Meduloblastoma/mortalidad , Meduloblastoma/secundario , Meduloblastoma/terapia , Retratamiento , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.