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 tumour. 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, SHH subtype). 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) 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 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 Zic1(+) 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 human WNT-subtype medulloblastoma. We provide 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 SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Gibson
authors.forename: Yiai
authors.initials: Y
authors.lastname: Tong
authors.forename: Giles
authors.initials: G
authors.lastname: Robinson
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Thompson
authors.forename: D Spencer
authors.initials: DS
authors.lastname: Currle
authors.forename: Christopher
authors.initials: C
authors.lastname: Eden
authors.forename: Tanya A
authors.initials: TA
authors.lastname: Kranenburg
authors.forename: Twala
authors.initials: T
authors.lastname: Hogg
authors.forename: Helen
authors.initials: H
authors.lastname: Poppleton
authors.forename: Julie
authors.initials: J
authors.lastname: Martin
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.forename: Aaron
authors.initials: A
authors.lastname: Weiss
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Patay
authors.forename: Matthew
authors.initials: M
authors.lastname: Scoggins
authors.forename: Robert
authors.initials: R
authors.lastname: Ogg
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Pei
authors.forename: Zeng-Jie
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Sonja
authors.initials: S
authors.lastname: Brun
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Frederique
authors.initials: F
authors.lastname: Zindy
authors.forename: Janet C
authors.initials: JC
authors.lastname: Lindsey
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Boop
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sanford
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Robert
authors.initials: R
authors.lastname: Wechsler-Reya
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000473:pathology*; D002528:Cerebellar Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051176:beta Catenin / Q000235:genetics
chemical_list: C495267:CTNNB1 protein, mouse; D051176:beta Catenin