Oncogene aberrations drive medulloblastoma progression, not initiation

Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge in paediatric neuro-oncology<sup>1</sup>. 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 prevail<sup>2,3</sup>. 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.

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Nature
Published
2025-05-07
DOI
https://doi.org/10.1038/s41586-025-08973-5
Citations
14
Primary Topic
Single-cell and spatial transcriptomics
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article
Field-Weighted Citation Impact
11.28
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article

Oncogene aberrations drive medulloblastoma progression, not initiation

Natalie Jaeger, Lena M. Kutscher, Kristian W. Pajtler, Lisa Nonnenmacher et al.
14 citations
Nature
Single-cell and spatial transcriptomics
11.28
article

Oncogene aberrations drive medulloblastoma progression, not initiation

Natalie Jaeger, Lena M. Kutscher, Kristian W. Pajtler, Lisa Nonnenmacher, Konrad Bochennek, Konstantin Okonechnikov, Stefan Rutkowski, Ioannis Sarropoulos, Andrea Wittmann, Supat Thongjuea, Frank Westermann, Piyush Joshi, Thomas Höfer, Jan Vaillant, David R. Ghasemi, Petra Fiesel, Tetsuya Yamada, Till Milde, Britta Statz, Patricia Benites Goncalves da Silva, Stefan M. Pfister, Anne Rademacher, Michele Bortolomeazzi, Mari Sepp, Jan‐Philipp Mallm, Karsten Rippe, Cornelis Martinus van Tilburg, Verena Körber, Ulrich Schüller, Mirjam Blattner-Johnson, Martin Mynarek, Katharina Johanna Weber, Henrik Kaessmann, David Jones, Olaf Witt, Andrey Korshunov, Barbara Jones, Christian Reimann, Kathrin Schramm
article en
14 citations

Abstract

Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge in paediatric neuro-oncology<sup>1</sup>. 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 prevail<sup>2,3</sup>. 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.

NatureVol. 642(8069)
Goethe University Frankfurt (DE), Universität Hamburg (DE), German Cancer Research Center (DE), Heidelberg University (DE), University Hospital Heidelberg (DE), University of Oxford (GB), University Medical Center Hamburg-Eppendorf (DE), Kinderkrebs-Zentrum Hamburg (DE), MRC Weatherall Institute of Molecular Medicine (GB), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), University Hospital Frankfurt (DE), DKFZ-ZMBH Alliance (DE), University Hospital Ulm (DE), Frankfurt Cancer Institute (DE), Deutsches Konsortium für Translationale Krebsforschung (DE)
Good health and well-being
Openalex Percentile: Top 1%
Single-cell and spatial transcriptomics
11.28
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