Subtypes of medulloblastoma have distinct developmental origins

Subtypes of medulloblastoma have distinct developmental origins

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 (GN...

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Main Authors: Gibson, Paul, Tong, Yiai, Robinson, Giles, Thompson, Margaret C., Currle, D. Spencer, Eden, Christopher, Kranenburg, Tanya A., Hogg, Twala, Poppleton, Helen, Martin, Julie, Finkelstein, David, Pounds, Stanley, Weiss, Aaron, Patay, Zoltan, Scoggins, Matthew, Ogg, Robert, Pei, Yanxin, Yang, Zeng-Jie, Brun, Sonja, Lee, Youngsoo, Zindy, Frederique, Lindsey, Janet C., Taketo, Makoto M., Boop, Frederick A., Sanford, Robert A., Gajjar, Amar, Clifford, Steven C., Roussel, Martine F., McKinnon, Peter J., Gutmann, David H., Ellison, David W., Wechsler-Reya, Robert, Gilbertson, Richard J.
Format: Online
Language:English
Published: 2010
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059767/
id pubmed-3059767
recordtype oai_dc
spelling pubmed-30597672011-06-23 Subtypes of medulloblastoma have distinct developmental origins Gibson, Paul Tong, Yiai Robinson, Giles Thompson, Margaret C. Currle, D. Spencer Eden, Christopher Kranenburg, Tanya A. Hogg, Twala Poppleton, Helen Martin, Julie Finkelstein, David Pounds, Stanley Weiss, Aaron Patay, Zoltan Scoggins, Matthew Ogg, Robert Pei, Yanxin Yang, Zeng-Jie Brun, Sonja Lee, Youngsoo Zindy, Frederique Lindsey, Janet C. Taketo, Makoto M. Boop, Frederick A. Sanford, Robert A. Gajjar, Amar Clifford, Steven C. Roussel, Martine F. McKinnon, Peter J. Gutmann, David H. Ellison, David W. Wechsler-Reya, Robert Gilbertson, Richard J. Article 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. 2010-12-08 2010-12-23 /pmc/articles/PMC3059767/ /pubmed/21150899 http://dx.doi.org/10.1038/nature09587 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Gibson, Paul
Tong, Yiai
Robinson, Giles
Thompson, Margaret C.
Currle, D. Spencer
Eden, Christopher
Kranenburg, Tanya A.
Hogg, Twala
Poppleton, Helen
Martin, Julie
Finkelstein, David
Pounds, Stanley
Weiss, Aaron
Patay, Zoltan
Scoggins, Matthew
Ogg, Robert
Pei, Yanxin
Yang, Zeng-Jie
Brun, Sonja
Lee, Youngsoo
Zindy, Frederique
Lindsey, Janet C.
Taketo, Makoto M.
Boop, Frederick A.
Sanford, Robert A.
Gajjar, Amar
Clifford, Steven C.
Roussel, Martine F.
McKinnon, Peter J.
Gutmann, David H.
Ellison, David W.
Wechsler-Reya, Robert
Gilbertson, Richard J.
spellingShingle Gibson, Paul
Tong, Yiai
Robinson, Giles
Thompson, Margaret C.
Currle, D. Spencer
Eden, Christopher
Kranenburg, Tanya A.
Hogg, Twala
Poppleton, Helen
Martin, Julie
Finkelstein, David
Pounds, Stanley
Weiss, Aaron
Patay, Zoltan
Scoggins, Matthew
Ogg, Robert
Pei, Yanxin
Yang, Zeng-Jie
Brun, Sonja
Lee, Youngsoo
Zindy, Frederique
Lindsey, Janet C.
Taketo, Makoto M.
Boop, Frederick A.
Sanford, Robert A.
Gajjar, Amar
Clifford, Steven C.
Roussel, Martine F.
McKinnon, Peter J.
Gutmann, David H.
Ellison, David W.
Wechsler-Reya, Robert
Gilbertson, Richard J.
Subtypes of medulloblastoma have distinct developmental origins
author_facet Gibson, Paul
Tong, Yiai
Robinson, Giles
Thompson, Margaret C.
Currle, D. Spencer
Eden, Christopher
Kranenburg, Tanya A.
Hogg, Twala
Poppleton, Helen
Martin, Julie
Finkelstein, David
Pounds, Stanley
Weiss, Aaron
Patay, Zoltan
Scoggins, Matthew
Ogg, Robert
Pei, Yanxin
Yang, Zeng-Jie
Brun, Sonja
Lee, Youngsoo
Zindy, Frederique
Lindsey, Janet C.
Taketo, Makoto M.
Boop, Frederick A.
Sanford, Robert A.
Gajjar, Amar
Clifford, Steven C.
Roussel, Martine F.
McKinnon, Peter J.
Gutmann, David H.
Ellison, David W.
Wechsler-Reya, Robert
Gilbertson, Richard J.
author_sort Gibson, Paul
title Subtypes of medulloblastoma have distinct developmental origins
title_short Subtypes of medulloblastoma have distinct developmental origins
title_full Subtypes of medulloblastoma have distinct developmental origins
title_fullStr Subtypes of medulloblastoma have distinct developmental origins
title_full_unstemmed Subtypes of medulloblastoma have distinct developmental origins
title_sort subtypes of medulloblastoma have distinct developmental origins
description 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.
publishDate 2010
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059767/
_version_ 1611445926829752320

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