TY  - JOUR
AU  - Okonechnikov, Konstantin
AU  - Joshi, Piyush Kumar
AU  - Körber, Verena
AU  - Rademacher, Anne
AU  - Bortolomeazzi, Michele
AU  - Mallm, Jan-Philipp
AU  - Vaillant, Jan
AU  - da Silva, Patricia Benites Goncalves
AU  - Statz, Britta
AU  - Sepp, Mari
AU  - Sarropoulos, Ioannis
AU  - Yamada, Tetsuya
AU  - Wittmann, Andrea
AU  - Schramm, Kathrin
AU  - Blattner-Johnson, Mirjam
AU  - Fiesel, Petra
AU  - Jones, Barbara
AU  - Jäger, Natalie
AU  - Milde, Till
AU  - Pajtler, Kristian
AU  - van Tilburg, Cornelis Martinus
AU  - Witt, Olaf
AU  - Bochennek, Konrad
AU  - Weber, Katharina Johanna
AU  - Nonnenmacher, Lisa
AU  - Reimann, Christian
AU  - Ghasemi, David R
AU  - Schüller, Ulrich
AU  - Mynarek, Martin
AU  - Rutkowski, Stefan
AU  - Jones, David
AU  - Korshunov, Andrey
AU  - Rippe, Karsten
AU  - Westermann, Frank
AU  - Thongjuea, Supat
AU  - Höfer, Thomas
AU  - Kaessmann, Henrik
AU  - Kutscher, Lena
AU  - Pfister, Stefan
TI  - Oncogene aberrations drive medulloblastoma progression, not initiation.
JO  - Nature
VL  - 642
IS  - 8069
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2025-00936
SP  - 1062-1072
PY  - 2025
N1  - DKFZ-ZMBH Alliance / #EA:B062#EA:B430#EA:B086#LA:B430#LA:B062# / 2025 Jun;642(8069):1062-1072
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40335697
DO  - DOI:10.1038/s41586-025-08973-5
UR  - https://inrepo02.dkfz.de/record/300822
ER  -