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  • 1
    Keywords: brain ; SONIC HEDGEHOG ; CENTRAL-NERVOUS-SYSTEM ; N-MYC ; BRAIN-TUMORS ; SUPPRESSOR GENE ; PRIMITIVE NEUROECTODERMAL TUMORS ; prospective ; CHILDHOOD MEDULLOBLASTOMA ; RISK STRATIFICATION ; EMBRYONAL TUMOR ; TRUE ROSETTES ETANTR
    Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, is currently diagnosed and stratified using a combination of clinical and demographic variables. Recent transcriptomic approaches have demonstrated that the histological entity known as medulloblastoma is comprised of multiple clinically and molecularly distinct subgroups. The current consensus is that four defined subgroups of medulloblastoma exist: WNT, SHH, Group 3, and Group 4. Each subgroup probably contains at least one additional level of hierarchy, with some evidence for multiple subtypes within each subgroup. The demographic and clinical differences between the subgroups present immediate and pressing questions to be addressed in the next round of clinical trials for patients with medulloblastoma. Many of the genetically defined targets for rational medulloblastoma therapies are unique to a given subgroup, suggesting the need for subgroup-specific trials of novel therapies. The development of practical, robust and widely accepted subgroup biomarkers that are amenable to the conditions of a prospective clinical trial is, therefore, an urgent need for the paediatric neuro-oncology community. In this Review, we discuss the clinical implications of molecular subgrouping in medulloblastoma, highlighting how these subgroups are transitioning from a research topic in the laboratory to a clinically relevant topic with important implications for patient care.
    Type of Publication: Journal article published
    PubMed ID: 22565209
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  • 2
    Keywords: CANCER ; CELLS ; DISTINCT ; CENTRAL-NERVOUS-SYSTEM ; METHYLATION ; ADULT ; BRAIN-TUMORS ; TELOMERASE ACTIVITY ; RISK STRATIFICATION ; SELF-RENEWAL
    Abstract: Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in 〈5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.
    Type of Publication: Journal article published
    PubMed ID: 24174164
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  • 3
    Keywords: CANCER ; CELLS ; DISEASE ; DISTINCT ; GENE-EXPRESSION ; MESSENGER-RNA ; alternative splicing ; WNT ; BRAIN-TUMORS ; medulloblastoma ; molecular diagnostics ; SUBGROUPS ; pediatric cancer ; BIOLOGICAL NETWORKS ; SHH ; Molecular subgroup ; Group 3 ; Group 4 ; BETA-2-CHIMAERIN ; Neuronal development
    Abstract: Medulloblastoma comprises four distinct molecular variants: WNT, SHH, Group 3, and Group 4. We analyzed alternative splicing usage in 14 normal cerebellar samples and 103 medulloblastomas of known subgroup. Medulloblastoma samples have a statistically significant increase in alternative splicing as compared to normal fetal cerebella (2.3-times; P 〈 6.47E-8). Splicing patterns are distinct and specific between molecular subgroups. Unsupervised hierarchical clustering of alternative splicing events accurately assigns medulloblastomas to their correct subgroup. Subgroup-specific splicing and alternative promoter usage was most prevalent in Group 3 (19.4%) and SHH (16.2%) medulloblastomas, while observed less frequently in WNT (3.2%), and Group 4 (9.3%) tumors. Functional annotation of alternatively spliced genes reveals overrepresentation of genes important for neuronal development. Alternative splicing events in medulloblastoma may be regulated in part by the correlative expression of antisense transcripts, suggesting a possible mechanism affecting subgroup-specific alternative splicing. Our results identify additional candidate markers for medulloblastoma subgroup affiliation, further support the existence of distinct subgroups of the disease, and demonstrate an additional level of transcriptional heterogeneity between medulloblastoma subgroups.
    Type of Publication: Journal article published
    PubMed ID: 22358458
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  • 4
    Keywords: TUMOR-SUPPRESSOR GENE ; CENTRAL-NERVOUS-SYSTEM ; ACQUIRED-RESISTANCE ; HIGH-DOSE CHEMOTHERAPY ; BRAIN-TUMORS ; PEDIATRIC MEDULLOBLASTOMA ; HEDGEHOG PATHWAY INHIBITOR ; DRIVEN MEDULLOBLASTOMA ; NEWLY-DIAGNOSED MEDULLOBLASTOMA ; MOLECULARLY DISTINCT
    Type of Publication: Journal article published
    PubMed ID: 23839353
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  • 5
    Keywords: POOR-PROGNOSIS ; BRAIN-TUMORS ; CHILDHOOD MEDULLOBLASTOMA ; RISK STRATIFICATION ; outcome prediction ; TP53 MUTATIONS ; PATHWAY ACTIVATION ; MOLECULAR SUBGROUPS ; NEUROTROPHIN RECEPTOR TRKC ; MYCN AMPLIFICATION
    Abstract: Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
    Type of Publication: Journal article published
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  • 6
    Keywords: HUMAN HOMOLOG ; SONIC HEDGEHOG ; CENTRAL-NERVOUS-SYSTEM ; BRAIN-TUMORS ; PRIMITIVE NEUROECTODERMAL TUMORS ; BASAL-CELL CARCINOMAS ; SPORADIC MEDULLOBLASTOMAS ; HEDGEHOG PATHWAY INHIBITOR ; LEWY-BODY FORMATION ; GORLIN SYNDROME
    Abstract: The division of medulloblastoma into different subgroups by microarray expression profiling has dramatically changed our perspective of this malignant childhood brain tumour. Now, the availability of next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup. The implications of these findings for the management of patients are readily apparent, pinpointing previously unappreciated diagnostic and therapeutic targets. In this Review, we summarize the 'explosion' of data emerging from the application of modern genomics to medulloblastoma, and in particular the recurrent targets of mutation in medulloblastoma subgroups. These data are currently making their way into clinical trials as we seek to integrate conventional and molecularly targeted therapies.
    Type of Publication: Journal article published
    PubMed ID: 23175120
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  • 7
    Keywords: ADVANCED SOLID TUMORS ; GENE-EXPRESSION ; BREAST-CANCER ; CYCLE PROGRESSION ; BRAIN-TUMORS ; GROWTH IN-VIVO ; CANCER STEM-CELLS ; NEURONAL PRECURSORS ; SMOOTHENED ANTAGONISTS ; PATHWAY INHIBITOR
    Abstract: Medulloblastoma is the most common malignant brain tumor in children. Although aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated medulloblastomas do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated medulloblastoma. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPC). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2-M phases of the cell cycle. Here, we show that CD15(+) cells progress more rapidly through the cell cycle than CD15(-) cells and contain an increased proportion of cells in G2-M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G2-M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. Our findings suggest that targeting G2-M regulators may represent a novel approach for treatment of human medulloblastoma. Cancer Res; 73(20); 6310-22. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 24067506
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