Medulloblastoma epigenetics and the path to clinical innovation
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TOPIC REVIEW
Medulloblastoma epigenetics and the path to clinical innovation Amanda R. Haltom1,4 · Stephanie A. Toll2 · Donghang Cheng1,4 · Shinji Maegawa1,4 · Vidya Gopalakrishnan1,3,4,5 · Soumen Khatua1,5 Received: 1 July 2020 / Accepted: 6 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Introduction In the last decade, a number of genomic and pharmacological studies have demonstrated the importance of epigenetic dysregulation in medulloblastoma initiation and progression. High throughput approaches including gene expression array, next-generation sequencing (NGS), and methylation profiling have now clearly identified at least four molecular subgroups within medulloblastoma, each with distinct clinical and prognostic characteristics. These studies have clearly shown that despite the overall paucity of mutations, clinically relevant events do occur within the cellular epigenetic machinery. Thus, this review aims to provide an overview of our current understanding of the spectrum of epi-oncogenetic perturbations in medulloblastoma. Methods Comprehensive review of epigenetic profiles of different subgroups of medulloblastoma in the context of molecular features. Summary Epigenetic regulation is mediated mainly by DNA methylation, histone modifications and microRNAs (miRNA). Importantly, epigenetic mis-events are reversible and have immense therapeutic potential. Conclusion The widespread epigenetic alterations present in these tumors has generated intense interest in their use as therapeutic targets. We provide an assessment of the progress that has been made towards the development of molecular subtypes-targeted therapies and the current status of clinical trials that have leveraged these recent advances. Keywords Medulloblastoma · Epigenetics · DNA methylation · Histone modifications · MicroRNA · Therapeutics
Introduction
Amanda R. Haltom and Stephanie A. Toll have contributed equally to this work. * Vidya Gopalakrishnan [email protected] * Soumen Khatua [email protected] 1
Division of Pediatrics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
2
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, USA
3
Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
4
Center for Cancer Epigenetics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
5
Brain Tumor Center, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Medulloblastoma (MB), a malignant embryonal tumor of childhood, accounts for 20% of all brain tumors in pediatrics [1]. Current multimodal treatment is associated with potential lifelong morbidities and a high risk for relapse [2]. Previous classification was based upon histopathological designations of classic, desmoplastic nodular, MB with extensive nodularity (MBEN), and large cell/anaplastic [2]. However, significant heterogeneity in outcomes exi
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