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Oncogene aberrations drive medulloblastoma progression, not initiation.

Konstantin Okonechnikov1,2,3, Piyush Joshi1,2,3,4, Verena Körber5,6

  • 1Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.

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|May 7, 2025
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Group 3/4 medulloblastoma treatment is challenging. Single-cell technologies reveal chromosomal aberrations initiate tumors early, while oncogene events like MYC emerge later, driving progression and resistance, aiding early diagnosis.

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Area of Science:

  • Paediatric neuro-oncology
  • Cancer genomics
  • Developmental neurobiology

Background:

  • Treatment for group 3/4 medulloblastoma, a challenging paediatric brain tumor, is hindered by significant intertumoural heterogeneity.
  • While some tumors have clear oncogenic drivers, most exhibit large-scale copy number aberrations, leaving the role of intratumoural heterogeneity and oncogene aberrations in tumor evolution and resistance poorly understood.

Purpose of the Study:

  • To investigate the interplay between chromosomal aberrations, oncogene alterations, and tumour evolution in group 3/4 medulloblastoma using single-cell technologies.
  • To understand the temporal dynamics of oncogenic events and their impact on treatment resistance.

Main Methods:

  • Single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing (snATAC-seq) were performed on group 3/4 medulloblastoma samples.
  • Spatial transcriptomics was employed to analyze the spatial distribution of tumour subclones.
  • A population genetics model was utilized to estimate the timing of medulloblastoma initiation.

Main Results:

  • Large-scale chromosomal aberrations were identified as early tumour-initiating events.
  • Single-gene oncogenic events, such as MYC, MYCN, and PRDM6 alterations, were found to arise later and are often subclonal, but MYC can become clonal during disease progression.
  • Spatial transcriptomics revealed that subclones are generally interspersed but can also show distinct segregation within the tumour.
  • Medulloblastoma initiation was estimated to occur in the cerebellar unipolar brush cell lineage during the first gestational trimester.

Conclusions:

  • Single-cell technologies provide critical insights into the complex evolutionary landscape of group 3/4 medulloblastoma.
  • Understanding the timing and clonal dynamics of genetic events is crucial for developing targeted therapies and improving treatment resistance strategies.
  • These findings highlight the potential of single-cell approaches for the early detection and diagnosis of this aggressive paediatric cancer.