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Neuro-oncology advances
2024 Jan-Dec;6 (1): vdae172.

Genomic tumor evolution dictates human medulloblastoma progression.

Yana Ruchiy, Ioanna Tsea, Efthalia Preka, Bronte Manouk Verhoeven, Thale Kristin Olsen, Shenglin Mei, Indranil Sinha, Klas Blomgren, Lena-Maria Carlson, Cecilia Dyberg, John Inge Johnsen, Ninib Baryawno
Author Information
  1. Yana Ruchiy: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. ORCID
  2. Ioanna Tsea: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  3. Efthalia Preka: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  4. Bronte Manouk Verhoeven: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  5. Thale Kristin Olsen: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  6. Shenglin Mei: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
  7. Indranil Sinha: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  8. Klas Blomgren: Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
  9. Lena-Maria Carlson: Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
  10. Cecilia Dyberg: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  11. John Inge Johnsen: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  12. Ninib Baryawno: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
PMID: 39659836 DOI: 10.1093/noajnl/vdae172

Abstract

Background: Medulloblastoma (MB) is the most common high-grade pediatric brain tumor, comprised of 4 main molecular subgroups-sonic-hedgehog (SHH), Wnt, Group 3, and Group 4. Group 3 and Group 4 tumors are the least characterized MB subgroups, despite Group 3 having the worst prognosis (~50% survival rate), and Group 4 being the most prevalent. Such poor characterization can be attributed to high levels of inter- and intratumoral heterogeneity, making it difficult to identify common therapeutic targets.
Methods: In this study, we generated single-cell sequencing data from 14 MB patients spanning all subgroups that we complemented with publicly available single-cell data from Group 3 patients. We used a ligand-receptor analysis tool (CellChat), expression- and allele-based copy-number variation (CNV) detection methods, and RNA velocity analysis to characterize tumor cell-cell interactions, established a connection between CNVs and temporal tumor progression, and unraveled tumor evolution.
Results: We show that MB tumor cells follow a temporal trajectory from those with low CNV levels to those with high CNV levels, allowing us to identify early and late markers for SHH, Group 3, and Group 4 MBs. Our study also identifies upregulation as a major event in later tumor clones for Group 3 and Group 4 MBs, suggesting it as a potential therapeutic target for both subgroups.
Conclusion: Taken together, our findings highlight MB's inherent tumor heterogeneity and offer promising insights into potential drivers of MB tumor evolution particularly in Group 3 and Group 4 MBs.

Keywords

medulloblastoma single-cell sequencing tumor heterogeneity

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