Embryonal Tumors of the Central Nervous System in Children: The Era of Targeted Therapeutics

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Abstract

Embryonal tumors (ET) of the central nervous system (CNS) in children encompass a wide clinical spectrum of aggressive malignancies. Until recently, the overlapping morphological features of these lesions posed a diagnostic challenge and undermined discovery of optimal treatment strategies. However, with the advances in genomic technology and the outpouring of biological data over the last decade, clear insights into the molecular heterogeneity of these tumors are now well delineated. The major subtypes of ETs of the CNS in children include medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and embryonal tumors with multilayered rosettes (ETMR), which are now biologically and clinically characterized as different entities. These important developments have paved the way for treatments guided by risk stratification as well as novel targeted therapies in efforts to improve survival and reduce treatment burden.

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Prediction of central nervous system embryonal tumour outcome based on gene expression.

Scott Pomeroy, Pablo Tamayo, Michelle Gaasenbeek … (2002)

Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.

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Subtypes of medulloblastoma have distinct developmental origins

Paul Gibson, Yiai Tong, Giles Robinson … (2010)

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor1–4. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype)3–8. The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype)1,3,4, arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

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Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.

Yoon-Jae Cho, Aviad Tsherniak, Pablo Tamayo … (2011)

Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors. We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets. Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals. Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.

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Journal

Journal ID (nlm-ta): Bioengineering (Basel)

Journal ID (iso-abbrev): Bioengineering (Basel)

Journal ID (publisher-id): bioengineering

Title: Bioengineering

Publisher: MDPI

ISSN (Electronic): 2306-5354

Publication date (Electronic): 23 September 2018

Publication date Collection: December 2018

Volume: 5

Issue: 4

Electronic Location Identifier: 78

Affiliations

[1 ]Section of Pediatric Hematology-Oncology, Department of Pediatrics, Wake Forest School of Medicine, Winston Salem, NC 27157, USA

[2 ]Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA; hendejac@ 123456ohsu.edu

[3 ]Department of Pediatrics, MD Anderson Cancer Center, Houston, TX 77030, USA; MBaig@ 123456mdanderson.org (M.B.); DChakraborty@ 123456mdanderson.org (D.C.); subhabis@ 123456gmail.com (S.B.); SKhatua@ 123456mdanderson.org (S.K.)

[4 ]Department of Pediatrics, Wake Forest School of Medicine, Winston Salem, NC 27157, USA; magardne@ 123456wakehealth.edu

[5 ]Humanitas University Medical School, 20090 Milan, Italy

Author notes

[* ]Correspondence: dkram@ 123456wakehealth.edu ; Tel.: +1-336-716-4085; Fax: +1-336-716-3010

[†]

These authors contributed equally the writing and preparation of the article.

Author information

Jacob J. Henderson https://orcid.org/0000-0002-3465-2256

Soumen Khatua https://orcid.org/0000-0001-6416-650X

Article

Publisher ID: bioengineering-05-00078

DOI: 10.3390/bioengineering5040078

PMC ID: 6315657

PubMed ID: 30249036

SO-VID: 3364c805-af62-4007-998d-7c246c949b9b

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Embryonal Tumors of the Central Nervous System in Children: The Era of Targeted Therapeutics

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Most cited references 98

Prediction of central nervous system embryonal tumour outcome based on gene expression.

Subtypes of medulloblastoma have distinct developmental origins

Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.

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