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Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker

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Abstract

Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients’ clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: “TCL1 MBEN” and “TCL2 MBEN” which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable “TCL1 MBEN” subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable “TCL2 MBEN” subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. “TCL2 MBEN” also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.

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Acknowledgements

The authors thank I. Leis, U. Lass, A. Habel, K. Lindenberg, and S. Kocher for excellent technical support and the microarray unit of the DKFZ Genomics and Proteomics Core Facility for providing Illumina DNA methylation array-related services. A. Korshunov is supported by the Helmholtz Association Research Grant (Germany, Grant no. HRSF-0005). M. Ryzhova, A. Golanov, and O. Zheludkova are supported by the RSF Research Grant no. 18-45-06012.

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Author notes

  1. Andrey Korshunov and Konstantin Okonechnikov contributed equally to this work.

Authors and Affiliations

  1. Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Andrey Korshunov, Felix Sahm, Damian Stichel, Daniel Schrimpf, Belen Casalini, Philipp Sievers, Jochen Meyer & Andreas von Deimling

  2. Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany

    Andrey Korshunov, Felix Sahm, Damian Stichel, Daniel Schrimpf, Belen Casalini, Philipp Sievers, Jochen Meyer & Andreas von Deimling

  3. Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Andrey Korshunov, Konstantin Okonechnikov, Felix Sahm, David R. Ghasemi, Kristian W. Pajtler, David T. W. Jones, Stefan M. Pfister, Marcel Kool & Andreas von Deimling

  4. Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Konstantin Okonechnikov, David R. Ghasemi, Kristian W. Pajtler, Stefan M. Pfister & Marcel Kool

  5. Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia

    Marina Ryzhova

  6. Department of radiological oncological and anatomic pathology sciences, Policlinico Umberto I Università Sapienza, Rome, Italy

    Manila Antonelli

  7. Pathology Unit, Ospedale Santobono-Pausilipon, Naples, Italy

    Vittoria Donofrio

  8. Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Rome, Italy

    Angela Mastronuzzi

  9. Department of Laboratories, Pathology Unit, Bambino Gesù Children’s Hospital, Rome, Italy

    Sabrina Rossi & Francesca Diomedi Camassei

  10. Pathology Unit, A. Meyer University Children’s Hospital, Florence, Italy

    Anna Maria Buccoliero

  11. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    Christine Haberler

  12. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

    Irene Slavc

  13. Division of Neuropathology, Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA

    Sonika Dahiya

  14. Department of Neuro-Oncology, Dmitry Rogachev National Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Ella Kumirova

  15. Department of Neuro-Oncology, Russian Scientific Center of Radiology, Moscow, Russia

    Olga Zheludkova

  16. Department of Neuroradiology, NN Burdenko Neurosurgical Institute, Moscow, Russia

    Andrey Golanov

  17. Pediatric Glioma Research Group (B360), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones

  18. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

    Stefan M. Pfister

  19. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Marcel Kool

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  1. Andrey Korshunov
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Korshunov, A., Okonechnikov, K., Sahm, F. et al. Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker. Acta Neuropathol 139, 583–596 (2020). https://doi.org/10.1007/s00401-019-02102-z

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