Oncogene aberrations drive medulloblastoma progression, not initiation

Konstantin Okonechnikov, Piyush Joshi, Verena Körber, Anne Rademacher, Michele Bortolomeazzi, Jan-Philipp Mallm, Jan Vaillant, Patricia Benites Goncalves Silva, Britta Statz, Mari Sepp, Ioannis Sarropoulos, Tetsuya Yamada, Andrea Wittmann, Kathrin Schramm, Mirjam Blattner-Johnson, Petra Fiesel, Barbara Jones, Natalie Jäger, Till Milde, Kristian W. Pajtler, Cornelis M. Tilburg, Olaf Witt, Konrad Bochennek, Katharina Johanna Weber, Lisa Nonnenmacher, Christian Reimann, David R. Ghasemi, Ulrich Schüller, Martin Mynarek, Stefan Rutkowski, David T. W. Jones, Andrey Korshunov, Karsten Rippe, Frank Westermann, Supat Thongjuea, Thomas Höfer, Henrik Kaessmann, Lena M. Kutscher () and Stefan M. Pfister ()
Additional contact information
Konstantin Okonechnikov: Hopp Children’s Cancer Center (KiTZ)
Piyush Joshi: Hopp Children’s Cancer Center (KiTZ)
Verena Körber: German Cancer Research Center (DKFZ)
Anne Rademacher: German Cancer Research Center (DKFZ) and Bioquant
Michele Bortolomeazzi: German Cancer Research Center (DKFZ)
Jan-Philipp Mallm: German Cancer Research Center (DKFZ)
Jan Vaillant: Hopp Children’s Cancer Center (KiTZ)
Patricia Benites Goncalves Silva: Hopp Children’s Cancer Center (KiTZ)
Britta Statz: Hopp Children’s Cancer Center (KiTZ)
Mari Sepp: DKFZ-ZMBH Alliance
Ioannis Sarropoulos: DKFZ-ZMBH Alliance
Tetsuya Yamada: DKFZ-ZMBH Alliance
Andrea Wittmann: Hopp Children’s Cancer Center (KiTZ)
Kathrin Schramm: Hopp Children’s Cancer Center (KiTZ)
Mirjam Blattner-Johnson: Hopp Children’s Cancer Center (KiTZ)
Petra Fiesel: Hopp Children’s Cancer Center (KiTZ)
Barbara Jones: Hopp Children’s Cancer Center (KiTZ)
Natalie Jäger: Hopp Children’s Cancer Center (KiTZ)
Till Milde: Hopp Children’s Cancer Center (KiTZ)
Kristian W. Pajtler: Hopp Children’s Cancer Center (KiTZ)
Cornelis M. Tilburg: Hopp Children’s Cancer Center (KiTZ)
Olaf Witt: Hopp Children’s Cancer Center (KiTZ)
Konrad Bochennek: Goethe University
Katharina Johanna Weber: Neurological Institute (Edinger Institute)
Lisa Nonnenmacher: University Children’s Hospital
Christian Reimann: University Children’s Hospital
David R. Ghasemi: Hopp Children’s Cancer Center (KiTZ)
Ulrich Schüller: University Medical Center Hamburg-Eppendorf
Martin Mynarek: University Medical Center Hamburg-Eppendorf
Stefan Rutkowski: University Medical Center Hamburg-Eppendorf
David T. W. Jones: Hopp Children’s Cancer Center (KiTZ)
Andrey Korshunov: Hopp Children’s Cancer Center (KiTZ)
Karsten Rippe: German Cancer Research Center (DKFZ) and Bioquant
Frank Westermann: Hopp Children’s Cancer Center (KiTZ)
Supat Thongjuea: Hopp Children’s Cancer Center (KiTZ)
Thomas Höfer: German Cancer Research Center (DKFZ)
Henrik Kaessmann: German Cancer Research Center (DKFZ)
Lena M. Kutscher: Hopp Children’s Cancer Center (KiTZ)
Stefan M. Pfister: Hopp Children’s Cancer Center (KiTZ)

Nature, 2025, vol. 642, issue 8069, 1062-1072

Abstract: Abstract Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge in paediatric neuro-oncology1. Bulk-omics approaches have identified considerable intertumoural heterogeneity in group 3/4 medulloblastoma, including the presence of clear single-gene oncogenic drivers in only a subset of cases, whereas in most cases, large-scale copy number aberrations prevail2,3. However, intratumoural heterogeneity, the role of oncogene aberrations, and broad copy number variation in tumour evolution and treatment resistance remain poorly understood. To dissect this interplay, we used single-cell technologies (single-nucleus RNA sequencing (snRNA-seq), single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing (snATAC-seq) and spatial transcriptomics) on a cohort of group 3/4 medulloblastoma with known alterations in the oncogenes MYC, MYCN and PRDM6. We show that large-scale chromosomal aberrations are early tumour-initiating events, whereas the single-gene oncogenic events arise late and are typically subclonal, but MYC can become clonal upon disease progression to drive further tumour development and therapy resistance. Spatial transcriptomics shows that the subclones are mostly interspersed across tumour tissue, but clear segregation is also present. Using a population genetics model, we estimate medulloblastoma initiation in the cerebellar unipolar brush cell lineage starting from the first gestational trimester. Our findings demonstrate how single-cell technologies can be applied for early detection and diagnosis of this fatal disease.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-08973-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:642:y:2025:i:8069:d:10.1038_s41586-025-08973-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-08973-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().