-
Cancer Cell Dec 2014Medulloblastoma (MB) is the most common malignant brain tumor in children, where one-third of patients succumb to their disease. This SnapShot describes the...
Medulloblastoma (MB) is the most common malignant brain tumor in children, where one-third of patients succumb to their disease. This SnapShot describes the classification of MB subgroups, historically by histopathology and currently based on genomic information. Genomics-based classification has identified four major subgroups and provides greater opportunity for developing targeted therapies more successful than current conventional therapy.
Topics: Animals; Cerebellar Neoplasms; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Medulloblastoma; Mice; Neoplasms, Experimental
PubMed: 25490452
DOI: 10.1016/j.ccell.2014.11.015 -
Neoplasia (New York, N.Y.) May 2023Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment,...
Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies. LMD may be diagnosed simultaneously with the primary tumor, at time of recurrence, or as primary LMD without a primary intraparenchymal lesion. Dissemination and seeding of the cerebrospinal fluid (CSF) involves a modified invasion-metastasis cascade and is often the result of direct deposition of tumor cells into the CSF. Cells develop select environmental advantages to survive the harsh, nutrient poor and turbulent environment of the CSF and leptomeninges. Improved understanding of the molecular mechanisms that underlie LMD, along with improved diagnostic and treatment approaches, will help the prognosis of children affected by primary brain tumors.
Topics: Child; Humans; Meningeal Neoplasms; Brain Neoplasms; Medulloblastoma; Prognosis; Cerebellar Neoplasms
PubMed: 37011459
DOI: 10.1016/j.neo.2023.100898 -
Cerebellum (London, England) Feb 2018Epigenetics is the process by which gene expression is regulated by events other than alterations of the genome. This includes DNA methylation, histone modifications,... (Review)
Review
Epigenetics is the process by which gene expression is regulated by events other than alterations of the genome. This includes DNA methylation, histone modifications, chromatin remodeling, microRNAs, and long non-coding RNAs. Methylation of DNA, chromatin remodeling, and histone modifications regulate the chromatin and access of transcription factors to DNA and in turn gene transcription. Alteration of chromatin is now recognized to be deregulated in many cancers. Medulloblastoma is an embryonal tumor of the cerebellum and the most common malignant brain tumor in children, that occurs only rarely in adults. Medulloblastoma is characterized by four major molecularly and histopathologically distinct groups, wingless (WNT), sonic hedgehog (SHH), group 3 (G3), and group 4 (G4), that, except for WNT, are each now subdivided in several subgroups. Gene expression array, next-generation sequencing, and methylation profiling of several hundred primary tumors by several consortia and independent groups revealed that medulloblastomas harbor a paucity of mutations most of which occur in epigenetic regulators, genetic alterations in oncogenes and tumor suppressors, in addition to copy number alterations and chromosome gains and losses. Remarkably, some tumors have no reported mutations, suggesting that some genes required for oncogenesis might be regulated by epigenetic mechanisms which are still to be uncovered and validated. This review will highlight several epigenetic regulators focusing mainly on histone modifiers identified in medulloblastoma.
Topics: Cerebellar Neoplasms; Epigenomics; Gene Expression Regulation, Neoplastic; Humans; Medulloblastoma; Signal Transduction
PubMed: 29178021
DOI: 10.1007/s12311-017-0899-9 -
Journal of the National Comprehensive... Aug 2023Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is... (Review)
Review
Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is disproportionately damaging to very young children. As a result, trials have attempted to delay, omit, and replace this therapy. Although success has been limited, the approach has not been a complete failure. In fact, this approach has cured a significant number of children with medulloblastoma. However, many children have endured intensive regimens of chemotherapy only to experience relapse and undergo salvage treatment with CSI, often at higher doses and with worse morbidity than they would have initially experienced. Recent advancements in molecular diagnostics have proven that response to therapy is biologically driven. Medulloblastoma in infants and young children is divided into 2 molecular groups: Sonic Hedgehog (SHH) and group 3 (G3). Both are chemotherapy-sensitive, but only the SHH medulloblastomas are reliably cured with chemotherapy alone. Moreover, SHH can be molecularly parsed into 2 groups: SHH-1 and SHH-2, with SHH-2 showing higher cure rates with less intensive chemotherapy and SHH-1 requiring more intensive regimens. G3 medulloblastoma, on the other hand, has a near universal relapse rate after chemotherapy-only regimens. This predictability represents a significant breakthrough and affords oncologists the ability to properly risk-stratify therapy in such a way that the most curative and least toxic therapy is selected. This review examines the treatment of medulloblastoma in infants and young children, discusses the molecular advancements, and proposes how to use this information to structure the future management of this disease.
Topics: Child; Infant; Humans; Adolescent; Child, Preschool; Medulloblastoma; Cerebellar Neoplasms; Hedgehog Proteins; Neoplasm Recurrence, Local; Recurrence
PubMed: 37643637
DOI: 10.6004/jnccn.2023.7024 -
Neuro-oncology Jan 2018Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across... (Review)
Review
Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), CSF cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined. We recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other Response Assessment in Neuro-Oncology recommendations, these need to now be prospectively validated in clinical trials.
Topics: Brain; Brain Neoplasms; Child; Humans; Medulloblastoma; Meningeal Neoplasms; Neoplasm Seeding; Neuroimaging
PubMed: 28449033
DOI: 10.1093/neuonc/nox087 -
Nature Reviews. Cancer Jan 2020Medulloblastoma, a malignant brain tumour primarily diagnosed during childhood, has recently been the focus of intensive molecular profiling efforts, profoundly... (Review)
Review
Medulloblastoma, a malignant brain tumour primarily diagnosed during childhood, has recently been the focus of intensive molecular profiling efforts, profoundly advancing our understanding of biologically and clinically heterogeneous disease subgroups. Genomic, epigenomic, transcriptomic and proteomic landscapes have now been mapped for an unprecedented number of bulk samples from patients with medulloblastoma and, more recently, for single medulloblastoma cells. These efforts have provided pivotal new insights into the diverse molecular mechanisms presumed to drive tumour initiation, maintenance and recurrence across individual subgroups and subtypes. Translational opportunities stemming from this knowledge are continuing to evolve, providing a framework for improved diagnostic and therapeutic interventions. In this Review, we summarize recent advances derived from this continued molecular characterization of medulloblastoma and contextualize this progress towards the deployment of more effective, molecularly informed treatments for affected patients.
Topics: Animals; Biomarkers, Tumor; Combined Modality Therapy; Disease Management; Disease Susceptibility; Epigenomics; Genetic Association Studies; Genomics; Humans; Medulloblastoma; Molecular Diagnostic Techniques; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Proteomics; Recurrence; Treatment Outcome; Tumor Microenvironment
PubMed: 31819232
DOI: 10.1038/s41568-019-0223-8 -
Indian Journal of Pathology &... May 2022Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either... (Review)
Review
Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either medulloblastoma or supratentorial primitive neuroectodermal tumors (PNETs). However, the application of DNA methylation/gene expression profiling in large series of neoplasms histologically defined as PNET, revealed tumors, which showed genetic events associated with glial tumors. These findings led to the definitive removal of the term "PNET" in the 2016 World Health Organization (WHO) classification of CNS tumors. Moreover, further studies on a large scale of methylation profiling have allowed the identification of new molecular-defined entities and have largely influenced the 5 edition of the WHO classification of CNS tumors (WHO CNS5) for both medulloblastomas and other CNS embryonal tumors. The importance of molecular characteristics in CNS embryonal tumors is well represented by the identification of different molecular groups and subgroups in medulloblastoma. So, in the CNS5, the emerged group 3 and group 4 belong to the classification, and the four molecular and morphologic types are now combined into a unique section. Among other embryonal tumors, two new recognized entities are introduced in CNS5: CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR internal tandem duplication (ITD). Embryonal tumor with multilayered rosettes (ETMR), already present in the previous classification now has a revised nomenclature as a result of the new DICER1 alteration, additional to the formerly known C19MC. Regarding atypical teratoid/rhabdoid tumor (AT/RT), three molecular subgroups are recognized in CNS5. The combination of histopathological and molecular features reflects the complexity of all these tumors and gives critical information in terms of prognosis and therapy. This encourages the use of a layered diagnostic report with the integrated diagnosis at the top, succeeded by layers including the histological, molecular, and other essential details.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Cerebellar Neoplasms; DEAD-box RNA Helicases; Forkhead Transcription Factors; Humans; Medulloblastoma; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive; Ribonuclease III; World Health Organization
PubMed: 35562137
DOI: 10.4103/ijpm.ijpm_1049_21 -
Neurologia Medico-chirurgica Nov 2016Medulloblastoma (MB) is one of the most frequent malignant brain tumors in children. The current standard treatment regimen consists of surgical resection, craniospinal... (Review)
Review
Medulloblastoma (MB) is one of the most frequent malignant brain tumors in children. The current standard treatment regimen consists of surgical resection, craniospinal irradiation, and adjuvant chemotherapy. Although these treatments have the potential to increase the survival of 70-80% of patients with MB, they are also associated with serious treatment-induced morbidity. The current risk stratification of MB is based on clinical factors, including age at presentation, metastatic status, and the presence of residual tumor following resection. In addition, recent genomic studies indicate that MB consists of at least four distinct molecular subgroups: WNT, sonic hedgehog (SHH), Group 3, and Group 4. WNT and SHH MBs are characterized by aberrations in the WNT and SHH signaling pathways, respectively. WNT MB has the best prognosis compared to the other MBs, while SHH MB has an intermediate prognosis. The underlying signaling pathways associated with Group 3 and 4 MBs have not been identified. Group 3 MB is frequently associated with metastasis, resulting in a poor prognosis, while Group 4 is sometimes associated with metastasis and has an intermediate prognosis. Group 4 is the most frequent MB and represents 35% of all MBs. These findings suggest that MB is a heterogeneous disease, and that MB subgroups have distinct molecular, demographic, and clinical characteristics. The molecular classification of MBs is redefining the risk stratification of patients with MB, and has the potential to identify new therapeutic strategies for the treatment of MB.
Topics: Cerebellar Neoplasms; Gene Expression Profiling; Humans; Medulloblastoma
PubMed: 27238212
DOI: 10.2176/nmc.ra.2016-0016 -
Cell Cycle (Georgetown, Tex.) Aug 2016The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1 mice as a medulloblastoma model, sequential mutations were found to shape tumor... (Review)
Review
The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1 mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations. Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma. This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth. Here we discuss in detail these 2 alternative mechanisms leading to medulloblastoma tumorigenesis.
Topics: Animals; Cellular Senescence; Hedgehog Proteins; Humans; Medulloblastoma; Mutation; Signal Transduction; Tumor Suppressor Protein p53
PubMed: 27229128
DOI: 10.1080/15384101.2016.1189044 -
Cancer Science Aug 2021Medulloblastoma is the most common malignant cerebellar tumor in children. Recent technological advances in multilayered 'omics data analysis have revealed 4 molecular... (Review)
Review
Medulloblastoma is the most common malignant cerebellar tumor in children. Recent technological advances in multilayered 'omics data analysis have revealed 4 molecular subgroups of medulloblastoma (Wingless/int, Sonic hedgehog, Group3, and Group4). (Epi)genomic and transcriptomic profiling on human primary medulloblastomas has shown distinct oncogenic drivers and cellular origin(s) across the subgroups. Despite tremendous efforts to identify the molecular signals driving tumorigenesis, few of the identified targets were druggable; therefore, a further understanding of the etiology of tumors is required to establish effective molecular-targeted therapies. Chromatin regulators are frequently mutated in medulloblastoma, prompting us to investigate epigenetic changes and the accompanying activation of oncogenic signaling during tumorigenesis. For this purpose, we have used germline and non-germline genetically engineered mice to model human medulloblastoma and to conduct useful, molecularly targeted, preclinical studies. This review discusses the biological implications of chromatin regulator mutations during medulloblastoma pathogenesis, based on recent in vivo animal studies.
Topics: Animals; Biomarkers, Tumor; Cerebellar Neoplasms; Chromatin; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Engineering; Humans; Medulloblastoma; Mice; Mutation
PubMed: 34050694
DOI: 10.1111/cas.14990