Abstract
Medulloblastoma is the most common pediatric malignant brain tumor. Advances in molecular profiling have uncovered significant heterogeneity among medulloblastomas and led to the identification of four distinct subgroups (wingless [WNT], sonic hedgehog [SHH], group 3, and group 4) that represent distinct disease entities in both underlying biology and clinical characteristics. The rapidly expanding repertoire of tools to study developmental and cancer biology is providing a wealth of knowledge about these embryonal tumors and is continuously refining the understanding of this complex cancer. In this review, the history of discovery in medulloblastoma is discussed, setting a foundation to outline the current state of understanding of the molecular underpinnings of this disease, with a focus on genomic events that define the aforementioned subgroups and evolving areas of focus, such as the cell of origin of medulloblastoma and medulloblastoma subtypes. With these recent discoveries in mind, the current state of medulloblastoma treatment and clinical trials is reviewed, including a novel risk stratification system that accounts for the molecular biomarkers of patients with a high risk for refractory disease. Lastly, critical areas of focus for future basic science and clinical research on this disease are discussed, such as the complexities of medulloblastoma metastases and recurrence as well as the priorities and strategies to implement in future clinical trials.
Highlights
Initial descriptions of medulloblastoma date back to Harvey Cushing, who initially described medulloblastoma as a subset of gliomas (Fig. 1).[2,11,57] He detailed many key features of these tumors, including their tendency to arise from the cerebellar vermis and to exhibit leptomeningeal metastasis.[11]
This tumor entered the molecular era, beginning with gene expression array studies demonstrating that medulloblastoma is a distinct entity from other embryonal central nervous system tumors.[47]
Multiple independent groups performed transcriptional profiling on medulloblastoma samples and reached consensus on four distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4.8,25,37,52,63 Molecular subgrouping has already influenced the design of contemporary clinical trials and refined preclinical studies of medulloblastoma, and these subgroups were adopted into the 2016 WHO classification of tumors of the central nervous system.[31]
Summary
Hypothesis that medulloblastoma and other PNETs arise from undifferentiated cells in the subependymal zone.[16]. Rapid advances in molecular genetics over the past two decades have provided significant advancements in our understanding of medulloblastoma This tumor entered the molecular era, beginning with gene expression array studies demonstrating that medulloblastoma is a distinct entity from other embryonal central nervous system tumors.[47] Multiple independent groups performed transcriptional profiling on medulloblastoma samples and reached consensus on four distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4.8,25,37,52,63 Molecular subgrouping has already influenced the design of contemporary clinical trials and refined preclinical studies of medulloblastoma, and these subgroups were adopted into the 2016 WHO classification of tumors of the central nervous system.[31] The expanding wealth of molecular data from patient samples has started to allow. SHH medulloblastomas may be initiated by germline mutations in PTCH1 (Gorlin syndrome), SUFU, TP53 (Li-Fraumeni syndrome), or SMO (Curry-Jones syndrome).[6,60,64,70] Numerous other cancer predisposition syndromes have been associated with medulloblastoma, with a lower risk of medulloblastoma development than the aforementioned syndromes associated with WNT and SHH tumors.[70]
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