Multiomic profiling of medulloblastoma reveals subtype-specific targetable alterations at the proteome and N-glycan level

Shweta Godbole, Hannah Voß, Antonia Gocke, Simon Schlumbohm, Yannis Schumann, Bojia Peng, Martin Mynarek, Stefan Rutkowski, Matthias Dottermusch, Mario M. Dorostkar, Andrey Korshunov, Thomas Mair, Stefan M. Pfister, Marcel Kwiatkowski, Madlen Hotze, Philipp Neumann, Christian Hartmann, Joachim Weis, Friederike Liesche-Starnecker, Yudong Guan, Manuela Moritz, Bente Siebels, Nina Struve, Hartmut Schlüter, Ulrich Schüller, Christoph Krisp and Julia E. Neumann ()
Additional contact information
Shweta Godbole: University Medical Center Hamburg-Eppendorf
Hannah Voß: University Medical Center Hamburg-Eppendorf
Antonia Gocke: University Medical Center Hamburg-Eppendorf
Simon Schlumbohm: Helmut Schmidt University
Yannis Schumann: Helmut Schmidt University
Bojia Peng: University Medical Center Hamburg-Eppendorf
Martin Mynarek: University Medical Center Hamburg-Eppendorf
Stefan Rutkowski: University Medical Center Hamburg-Eppendorf
Matthias Dottermusch: University Medical Center Hamburg-Eppendorf
Mario M. Dorostkar: Ludwig-Maximilians-University
Andrey Korshunov: University Hospital Heidelberg
Thomas Mair: University Medical Center Hamburg-Eppendorf
Stefan M. Pfister: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Marcel Kwiatkowski: University of Innsbruck
Madlen Hotze: University of Innsbruck
Philipp Neumann: Helmut Schmidt University
Christian Hartmann: Hannover Medical School (MHH)
Joachim Weis: RWTH Aachen University Hospital
Friederike Liesche-Starnecker: University of Augsburg
Yudong Guan: University Medical Center Hamburg-Eppendorf
Manuela Moritz: University Medical Center Hamburg-Eppendorf
Bente Siebels: University Medical Center Hamburg-Eppendorf
Nina Struve: University Medical Center Hamburg-Eppendorf
Hartmut Schlüter: University Medical Center Hamburg-Eppendorf
Ulrich Schüller: University Medical Center Hamburg-Eppendorf
Christoph Krisp: University Medical Center Hamburg-Eppendorf
Julia E. Neumann: University Medical Center Hamburg-Eppendorf

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: Abstract Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically heterogenous. The application of omics technologies—mainly studying nucleic acids—has significantly improved MB classification and stratification, but treatment options are still unsatisfactory. The proteome and their N-glycans hold the potential to discover clinically relevant phenotypes and targetable pathways. We compile a harmonized proteome dataset of 167 MBs and integrate findings with DNA methylome, transcriptome and N-glycome data. We show six proteome MB subtypes, that can be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pG3myc), and synapses/immunological processes (pSHHs, pG3 and pG4). Multiomic analysis reveals different conservation levels of proteome features across MB subtypes at the DNA methylome level. Aggressive pGroup3myc MBs and favorable pWNT MBs are most similar in cluster hierarchies concerning overall proteome patterns but show different protein abundances of the vincristine resistance-associated multiprotein complex TriC/CCT and of N-glycan turnover-associated factors. The N-glycome reflects proteome subtypes and complex-bisecting N-glycans characterize pGroup3myc tumors. Our results shed light on targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.

Date: 2024
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DOI: 10.1038/s41467-024-50554-z

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