Subtypes of medulloblastoma have distinct developmental origins

Paul Gibson, Yiai Tong, Giles Robinson, Margaret C. Thompson, D. Spencer Currle, Christopher Eden, Tanya A. Kranenburg, Twala Hogg, Helen Poppleton, Julie Martin, David Finkelstein, Stanley Pounds, Aaron Weiss, Zoltan Patay, Matthew Scoggins, Robert Ogg, Yanxin Pei, Zeng Jie Yang, Sonja Brun, Youngsoo LeeFrederique Zindy, Janet C. Lindsey, Makoto M. Taketo, Frederick Boop, Robert A. Sanford, Amar Gajjar, Steven C. Clifford, Martine F. Rousse, Peter J. McKinnon, David H. Gutmann, David W. Ellison, Robert Wechsler-Reya, Richard J. Gilbertson

Research output: Contribution to journalArticle

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Abstract

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour1-4. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHHsubtype)3-8. The pathologicalprocesses that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development ofmuch needed newtherapies.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 WNTsubtype 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 tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours 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 which included aberrantly proliferating Zicl+ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of humanWNT-subtypemedulloblastoma.Weprovide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins.Our data provide an explanation for the marked molecular and clinical differences between SHHand WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

Original languageEnglish (US)
Pages (from-to)1095-1099
Number of pages5
JournalNature
Volume468
Issue number7327
DOIs
StatePublished - Dec 23 2010

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Medulloblastoma
Cerebellum
Brain Stem
Neoplasms
Lip
Mutation
Hedgehogs
Transcriptome
Anatomy
Stem Cells
Magnetic Resonance Imaging
Neurons
Brain
Population
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Gibson, P., Tong, Y., Robinson, G., Thompson, M. C., Currle, D. S., Eden, C., ... Gilbertson, R. J. (2010). Subtypes of medulloblastoma have distinct developmental origins. Nature, 468(7327), 1095-1099. https://doi.org/10.1038/nature09587

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; Sanford, Robert A.; Gajjar, Amar; Clifford, Steven C.; Rousse, Martine F.; McKinnon, Peter J.; Gutmann, David H.; Ellison, David W.; Wechsler-Reya, Robert; Gilbertson, Richard J.

In: Nature, Vol. 468, No. 7327, 23.12.2010, p. 1095-1099.

Research output: Contribution to journalArticle

Gibson, P, Tong, Y, Robinson, G, Thompson, MC, Currle, DS, Eden, C, Kranenburg, TA, Hogg, T, Poppleton, H, Martin, J, Finkelstein, D, Pounds, S, Weiss, A, Patay, Z, Scoggins, M, Ogg, R, Pei, Y, Yang, ZJ, Brun, S, Lee, Y, Zindy, F, Lindsey, JC, Taketo, MM, Boop, F, Sanford, RA, Gajjar, A, Clifford, SC, Rousse, MF, McKinnon, PJ, Gutmann, DH, Ellison, DW, Wechsler-Reya, R & Gilbertson, RJ 2010, 'Subtypes of medulloblastoma have distinct developmental origins', Nature, vol. 468, no. 7327, pp. 1095-1099. https://doi.org/10.1038/nature09587
Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010 Dec 23;468(7327):1095-1099. https://doi.org/10.1038/nature09587
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 ; Sanford, Robert A. ; Gajjar, Amar ; Clifford, Steven C. ; Rousse, Martine F. ; McKinnon, Peter J. ; Gutmann, David H. ; Ellison, David W. ; Wechsler-Reya, Robert ; Gilbertson, Richard J. / Subtypes of medulloblastoma have distinct developmental origins. In: Nature. 2010 ; Vol. 468, No. 7327. pp. 1095-1099.
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title = "Subtypes of medulloblastoma have distinct developmental origins",
abstract = "Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour1-4. These tumours are thought to arise within the cerebellum, with approximately 25{\%} originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHHsubtype)3-8. The pathologicalprocesses that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development ofmuch needed newtherapies.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 WNTsubtype 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 tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours 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 which included aberrantly proliferating Zicl+ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15{\%} of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of humanWNT-subtypemedulloblastoma.Weprovide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins.Our data provide an explanation for the marked molecular and clinical differences between SHHand WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.",
author = "Paul Gibson and Yiai Tong and Giles Robinson and Thompson, {Margaret C.} and Currle, {D. Spencer} and Christopher Eden and Kranenburg, {Tanya A.} and Twala Hogg and Helen Poppleton and Julie Martin and David Finkelstein and Stanley Pounds and Aaron Weiss and Zoltan Patay and Matthew Scoggins and Robert Ogg and Yanxin Pei and Yang, {Zeng Jie} and Sonja Brun and Youngsoo Lee and Frederique Zindy and Lindsey, {Janet C.} and Taketo, {Makoto M.} and Frederick Boop and Sanford, {Robert A.} and Amar Gajjar and Clifford, {Steven C.} and Rousse, {Martine F.} and McKinnon, {Peter J.} and Gutmann, {David H.} and Ellison, {David W.} and Robert Wechsler-Reya and Gilbertson, {Richard J.}",
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T1 - Subtypes of medulloblastoma have distinct developmental origins

AU - Gibson, Paul

AU - Tong, Yiai

AU - Robinson, Giles

AU - Thompson, Margaret C.

AU - Currle, D. Spencer

AU - Eden, Christopher

AU - Kranenburg, Tanya A.

AU - Hogg, Twala

AU - Poppleton, Helen

AU - Martin, Julie

AU - Finkelstein, David

AU - Pounds, Stanley

AU - Weiss, Aaron

AU - Patay, Zoltan

AU - Scoggins, Matthew

AU - Ogg, Robert

AU - Pei, Yanxin

AU - Yang, Zeng Jie

AU - Brun, Sonja

AU - Lee, Youngsoo

AU - Zindy, Frederique

AU - Lindsey, Janet C.

AU - Taketo, Makoto M.

AU - Boop, Frederick

AU - Sanford, Robert A.

AU - Gajjar, Amar

AU - Clifford, Steven C.

AU - Rousse, Martine F.

AU - McKinnon, Peter J.

AU - Gutmann, David H.

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AB - Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour1-4. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHHsubtype)3-8. The pathologicalprocesses that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development ofmuch needed newtherapies.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 WNTsubtype 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 tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours 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 which included aberrantly proliferating Zicl+ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of humanWNT-subtypemedulloblastoma.Weprovide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins.Our data provide an explanation for the marked molecular and clinical differences between SHHand WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

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