Oncogene aberrations drive medulloblastoma progression, not initiation.

in Nature by Konstantin Okonechnikov, Piyush Joshi, Verena Körber, Anne Rademacher, Michele Bortolomeazzi, Jan-Philipp Mallm, Jan Vaillant, Patricia Benites Goncalves da 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 van 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, Stefan M Pfister

TLDR

  • The study used advanced techniques to understand the complexities of group 3/4 medulloblastoma, a deadly brain tumor in children. The findings suggest that early detection and diagnosis may be possible using single-cell technologies.

Abstract

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

Overview

  • The study aimed to understand the heterogeneity and evolution of group 3/4 medulloblastoma, a challenging pediatric brain tumor to treat.
  • The researchers used single-cell technologies, including single-nucleus RNA sequencing, single-nucleus assay for transposase-accessible chromatin, and spatial transcriptomics, to analyze a cohort of group 3/4 medulloblastoma patients with known alterations in the oncogenes MYC, MYCN, and PRDM6.
  • The study aimed to dissect the interplay between intertumoural and intratumoural heterogeneity, oncogene aberrations, and broad copy number variation in tumour evolution and treatment resistance.

Comparative Analysis & Findings

  • The study found that large-scale chromosomal aberrations are early tumour-initiating events, whereas single-gene oncogenic events arise late and are typically subclonal, except for MYC, which can become clonal upon disease progression.
  • Spatial transcriptomics revealed that subclones are mostly interspersed across tumour tissue, but clear segregation is also present.
  • The study estimated medulloblastoma initiation in the cerebellar unipolar brush cell lineage starting from the first gestational trimester using a population genetics model.

Implications and Future Directions

  • The findings demonstrate the potential of single-cell technologies for early detection and diagnosis of group 3/4 medulloblastoma, a fatal disease.
  • The study highlights the importance of understanding intertumoural and intratumoural heterogeneity, oncogene aberrations, and copy number variation in tumour evolution and treatment resistance.
  • Future studies can build on these findings to develop targeted therapies and improve treatment outcomes for group 3/4 medulloblastoma patients.
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