Chromosomal Instability Characterizes Pediatric Medulloblastoma but Is Not Tolerated in the Developing Cerebellum

Irena Bockaj, Tosca E. Martini, Marlinde J. Smit, Inna Armandari, Bjorn Bakker, Rene Wardenaar, Tiny G. J. Meeuwsen-de Boer, Petra L. Bakker, Diana C. J. Spierings, Eelco W. Hoving, Victor Guryev, Floris Foijer, Sophia W. M. Bruggeman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Medulloblastoma is a pediatric brain malignancy that consists of four transcriptional subgroups. Structural and numerical aneuploidy are common in all subgroups, although they are particularly profound in Group 3 and Group 4 medulloblastoma and in a subtype of SHH medulloblastoma termed SHH alpha. This suggests that chromosomal instability (CIN), the process leading to aneuploidy, is an important player in medulloblastoma pathophysiology. However, it is not known if there is ongoing CIN in medulloblastoma or if CIN affects the developing cerebellum and promotes tumor formation. To investigate this, we performed karyotyping of single medulloblastoma cells and demonstrated the presence of distinct tumor cell clones harboring unique copy number alterations, which is suggestive of ongoing CIN. We also found enrichment for processes related to DNA replication, repair, and mitosis in both SHH medulloblastoma and in the highly proliferative compartment of the presumed tumor cell lineage-of-origin, the latter also being sensitive to genotoxic stress. However, when challenging these tumor cells-of-origin with genetic lesions inducing CIN using transgenic mouse modeling, we found no evidence for large chromosomal aberrations in the cerebellum or for medulloblastoma formation. We therefore conclude that without a background of specific genetic mutations, CIN is not tolerated in the developing cerebellum in vivo and, thus, by itself is not sufficient to initiate medulloblastoma.

Original languageEnglish
Article number9852
Number of pages15
JournalInternational Journal of Molecular Sciences
Volume23
Issue number17
DOIs
Publication statusPublished - 30-Aug-2022

Keywords

  • medulloblastoma
  • genomic instability
  • chromosomal instability
  • aneuploidy
  • genotoxic stress
  • cerebellar granule neuron progenitors
  • cerebellar development
  • SONIC HEDGEHOG
  • SPINDLE CHECKPOINT
  • CELL-PROLIFERATION
  • MOUSE MODEL
  • STEM
  • NEUROGENESIS
  • EXPRESSION
  • ANEUPLOIDY
  • LANDSCAPE
  • SUBGROUP

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