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Pediatric and Developmental Pathology :... 2022In 2016, medulloblastoma classification was restructured to allow for incorporation of updated data about medulloblastoma biology, genomics, and clinical behavior. For... (Review)
Review
In 2016, medulloblastoma classification was restructured to allow for incorporation of updated data about medulloblastoma biology, genomics, and clinical behavior. For the first time, medulloblastomas were classified according to molecular characteristics ("genetically defined" categories) as well as histologic characteristics ("histologically defined" categories). Current genetically-defined categories include WNT-activated, SHH-activated wildtype, SHH-activated -mutant, and non-WNT/non-SHH. In this article, we review the most recent update to the classification of medulloblastomas, provide a practical approach to immunohistochemical and molecular testing for these tumors, and demonstrate how to use key molecular genetic findings to develop an integrated diagnosis.
Topics: Cerebellar Neoplasms; Humans; Medulloblastoma; World Health Organization
PubMed: 35168417
DOI: 10.1177/10935266211018931 -
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 -
Nature Protocols Jul 2023Medulloblastoma and high-grade glioma represent the most aggressive and frequent lethal solid tumors affecting individuals during pediatric age. During the past years,... (Review)
Review
Medulloblastoma and high-grade glioma represent the most aggressive and frequent lethal solid tumors affecting individuals during pediatric age. During the past years, several models have been established for studying these types of cancers. Human organoids have recently been shown to be a valid alternative model to study several aspects of brain cancer biology, genetics and test therapies. Notably, brain cancer organoids can be generated using genetically modified cerebral organoids differentiated from human induced pluripotent stem cells (hiPSCs). However, the protocols to generate them and their downstream applications are very rare. Here, we describe the protocols to generate cerebellum and forebrain organoids from hiPSCs, and the workflow to genetically modify them by overexpressing genes found altered in patients to finally produce cancer organoids. We also show detailed protocols to use medulloblastoma and high-grade glioma organoids for orthotopic transplantation and co-culture experiments aimed to study cell biology in vivo and in vitro, for lineage tracing to investigate the cell of origin and for drug screening. The protocol takes 60-65 d for cancer organoids generation and from 1-4 weeks for downstream applications. The protocol requires at least 3-6 months to become proficient in culturing hiPSCs, generating organoids and performing procedures on immunodeficient mice.
Topics: Humans; Child; Animals; Mice; Medulloblastoma; Coculture Techniques; Drug Evaluation, Preclinical; Induced Pluripotent Stem Cells; Glioma; Organoids; Brain Neoplasms; Prosencephalon; Cell Differentiation; Cerebellar Neoplasms
PubMed: 37248391
DOI: 10.1038/s41596-023-00839-2 -
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 -
The Lancet. Oncology Dec 2019The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of... (Review)
Review
The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
Topics: Adolescent; Adult; Cerebellar Neoplasms; Europe; Follow-Up Studies; Humans; Medulloblastoma; Practice Guidelines as Topic; Puberty
PubMed: 31797797
DOI: 10.1016/S1470-2045(19)30669-2 -
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 -
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 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 Apr 2020Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers...
Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MB) ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MB. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U) position. Tumours from patients with ELP1-associated MB were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
Topics: Cerebellar Neoplasms; Child; Female; Germ-Line Mutation; Humans; Male; Medulloblastoma; Pedigree; RNA, Transfer; Transcriptional Elongation Factors
PubMed: 32296180
DOI: 10.1038/s41586-020-2164-5