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Journal of Child Neurology Oct 2016Medulloblastoma accounts for nearly 10% of all childhood brain tumors. These tumors occur exclusively in the posterior fossa and have the potential for leptomeningeal... (Review)
Review
Medulloblastoma accounts for nearly 10% of all childhood brain tumors. These tumors occur exclusively in the posterior fossa and have the potential for leptomeningeal spread. Treatment includes a combination of surgery, radiation therapy (in patients >3 years old). Patients >3 years old are stratified based on the volume of postoperative residual tumor and the presence or absence of metastases into "standard risk" and "high risk" categories with long-term survival rates of approximately 85% and 70%, respectively. Outcomes are inferior in infants and children younger than 3 years with exception of those patients with the medulloblastoma with extensive nodularity histologic subtype. Treatment for medulloblastoma is associated with significant morbidity, especially in the youngest patients. Recent molecular subclassification of medulloblastoma has potential prognostic and therapeutic implications. Future incorporation of molecular subgroups into treatment protocols will hopefully improve both survival outcomes and posttreatment quality of life.
Topics: Brain Neoplasms; Child; Child, Preschool; Humans; Infant; Medulloblastoma
PubMed: 26336203
DOI: 10.1177/0883073815600866 -
Cancer Cell Jun 2017While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF)...
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.
Topics: Cluster Analysis; Cohort Studies; DNA Copy Number Variations; DNA Methylation; Gene Expression Profiling; Genomics; Humans; Medulloblastoma; Precision Medicine
PubMed: 28609654
DOI: 10.1016/j.ccell.2017.05.005 -
Brain Pathology (Zurich, Switzerland) May 2020Medulloblastoma (MB) is the most common CNS embryonal tumor. While the overall cure rate is around 70%, patients with high-risk disease continue to have poor outcome and... (Review)
Review
Medulloblastoma (MB) is the most common CNS embryonal tumor. While the overall cure rate is around 70%, patients with high-risk disease continue to have poor outcome and experience long-term morbidity. MB is among the tumors for which diagnosis, risk stratification, and clinical management has shown the most rapid advancement. These advances are largely due to technological improvements in diagnosis and risk stratification which now integrate histomorphologic classification and molecular classification. MB stands as a prototype for other solid tumors in how to effectively integrate morphology and genomic data to stratify clinicopathologic risk and aid design of innovative clinical trials for precision medicine. This review explores the current diagnostic and classification of MB in modern neuropathology laboratories.
Topics: Cerebellar Neoplasms; Humans; Medulloblastoma
PubMed: 32239782
DOI: 10.1111/bpa.12837 -
Current Neurology and Neuroscience... Dec 2023Review recent advances in the understanding of pediatric medulloblastoma including etiology, biology, radiology, and management of pediatric medulloblastoma. (Review)
Review
PURPOSE OF REVIEW
Review recent advances in the understanding of pediatric medulloblastoma including etiology, biology, radiology, and management of pediatric medulloblastoma.
RECENT FINDINGS
The classic four subgroups have been reclassified and further subdivided based on new molecular findings. Research is revealing the cell origins of the different subtypes of medulloblastoma. There has been continued personalization of management based on molecular parameters. While many advances have been made in the knowledge base of this most common malignant pediatric brain tumor, there has not yet been translation into more effective therapies to prolong survival in all subgroups with the possible exception of children with group 3 disease. Quality of life remains a major challenge for long-term survivors.
Topics: Child; Humans; Medulloblastoma; Quality of Life; Brain Neoplasms; Cerebellar Neoplasms
PubMed: 37943476
DOI: 10.1007/s11910-023-01316-9 -
Cancer Cell Dec 2022MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased...
MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
Topics: Child; Humans; Medulloblastoma; Dihydroorotate Dehydrogenase; Cell Line, Tumor; Neoplasm Recurrence, Local; Pyrimidines; Cerebellar Neoplasms
PubMed: 36368321
DOI: 10.1016/j.ccell.2022.10.009 -
Nature Aug 2019Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well...
Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
Topics: Adolescent; Adult; Animals; Cell Lineage; Cerebellum; Child; Child, Preschool; DNA Copy Number Variations; Gene Expression Regulation, Neoplastic; Genomics; Glutamic Acid; Humans; Infant; Medulloblastoma; Mice; Neurons; Single-Cell Analysis; Transcriptome
PubMed: 31341285
DOI: 10.1038/s41586-019-1434-6 -
Acta Neuropathologica Jun 2016Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of... (Review)
Review
Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3-17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75-90 % survival), high risk (50-75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or MYCN-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with TP53 mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.
Topics: Adolescent; Biomarkers, Tumor; Cerebellar Neoplasms; Child; Child, Preschool; Gene Expression Profiling; Humans; Medulloblastoma; Prognosis; Risk Factors
PubMed: 27040285
DOI: 10.1007/s00401-016-1569-6 -
Cancer Cell Sep 2019Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we...
Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2 progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2 progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2 progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Child, Preschool; Datasets as Topic; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene Regulatory Networks; Hedgehog Proteins; Humans; Male; Medulloblastoma; Mice, Transgenic; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Neuroglia; Oligodendrocyte Transcription Factor 2; Prognosis; RNA-Seq; Signal Transduction; Single-Cell Analysis; Survival Analysis; Transcriptome
PubMed: 31474569
DOI: 10.1016/j.ccell.2019.07.009 -
Nature Sep 2022Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to...
Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins. However, the anatomical and cellular complexity of developing human tissues-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.
Topics: Animals; Cell Lineage; Cerebellar Neoplasms; Cerebellum; Humans; Medulloblastoma; Metencephalon; Mice; Neurons; Prospective Studies
PubMed: 36131015
DOI: 10.1038/s41586-022-05208-9 -
Cancer Cell Sep 2018Epigenomics and transcriptomics of medulloblastoma-an important childhood brain tumor-segregate the disease into four clinically relevant subtypes. In this issue of...
Epigenomics and transcriptomics of medulloblastoma-an important childhood brain tumor-segregate the disease into four clinically relevant subtypes. In this issue of Cancer Cell, Archer et al. and Forget et al. add the proteome to our multiomic map of this disease, revealing posttranscriptional and posttranslational variations with potential therapeutic implications.
Topics: Brain Neoplasms; Cerebellar Neoplasms; Child; Humans; Medulloblastoma; Receptor, ErbB-4; Signal Transduction
PubMed: 30205039
DOI: 10.1016/j.ccell.2018.08.010