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The whole-genome landscape of medulloblastoma subtypes.

ABSTRACT: Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

SUBMITTER: Northcott PA

PROVIDER: S-EPMC5905700 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The whole-genome landscape of medulloblastoma subtypes.

Northcott Paul A PA Buchhalter Ivo I Morrissy A Sorana AS Hovestadt Volker V Weischenfeldt Joachim J Ehrenberger Tobias T Gröbner Susanne S Segura-Wang Maia M Zichner Thomas T Rudneva Vasilisa A VA Warnatz Hans-Jörg HJ Sidiropoulos Nikos N Phillips Aaron H AH Schumacher Steven S Kleinheinz Kortine K Waszak Sebastian M SM Erkek Serap S Jones David T W DTW Worst Barbara C BC Kool Marcel M Zapatka Marc M Jäger Natalie N Chavez Lukas L Hutter Barbara B Bieg Matthias M Paramasivam Nagarajan N Heinold Michael M Gu Zuguang Z Ishaque Naveed N Jäger-Schmidt Christina C Imbusch Charles D CD Jugold Alke A Hübschmann Daniel D Risch Thomas T Amstislavskiy Vyacheslav V Gonzalez Francisco German Rodriguez FGR Weber Ursula D UD Wolf Stephan S Robinson Giles W GW Zhou Xin X Wu Gang G Finkelstein David D Liu Yanling Y Cavalli Florence M G FMG Luu Betty B Ramaswamy Vijay V Wu Xiaochong X Koster Jan J Ryzhova Marina M Cho Yoon-Jae YJ Pomeroy Scott L SL Herold-Mende Christel C Schuhmann Martin M Ebinger Martin M Liau Linda M LM Mora Jaume J McLendon Roger E RE Jabado Nada N Kumabe Toshihiro T Chuah Eric E Ma Yussanne Y Moore Richard A RA Mungall Andrew J AJ Mungall Karen L KL Thiessen Nina N Tse Kane K Wong Tina T Jones Steven J M SJM Witt Olaf O Milde Till T Von Deimling Andreas A Capper David D Korshunov Andrey A Yaspo Marie-Laure ML Kriwacki Richard R Gajjar Amar A Zhang Jinghui J Beroukhim Rameen R Fraenkel Ernest E Korbel Jan O JO Brors Benedikt B Schlesner Matthias M Eils Roland R Marra Marco A MA Pfister Stefan M SM Taylor Michael D MD Lichter Peter P

Nature 20170701 7663

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigeneti ...[more]

PMID: 28726821

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Project description: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.

Dataset Information

The whole-genome landscape of medulloblastoma subtypes.

Publications

The whole-genome landscape of medulloblastoma subtypes.

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