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, Julia E Neumann
Author Information
Shweta Godbole: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
Hannah Voß: Section of Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Antonia Gocke: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
Simon Schlumbohm: Chair for High Performance Computing, Helmut Schmidt University, Hamburg, Germany.
Yannis Schumann: Chair for High Performance Computing, Helmut Schmidt University, Hamburg, Germany. ORCID
Bojia Peng: Section of Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Martin Mynarek: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
Stefan Rutkowski: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Matthias Dottermusch: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
Mario M Dorostkar: Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany.
Andrey Korshunov: Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
Thomas Mair: Section of Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Stefan M Pfister: Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany. ORCID
Marcel Kwiatkowski: Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria. ORCID
Madlen Hotze: Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria.
Philipp Neumann: Chair for High Performance Computing, Helmut Schmidt University, Hamburg, Germany. ORCID
Christian Hartmann: Department of Neuropathology, Hannover Medical School (MHH), Hannover, Germany.
Joachim Weis: Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany. ORCID
Friederike Liesche-Starnecker: Pathology, Medical Faculty, University of Augsburg, Augsburg, Germany.
Yudong Guan: Section of Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Manuela Moritz: Section of Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Bente Siebels: Section of Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Nina Struve: Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hartmut Schlüter: Section of Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ulrich Schüller: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
Christoph Krisp: Section of Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ORCID
Julia E Neumann: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ju.neumann@uke.de. ORCID
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.
