Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers

Research output: Contribution to journalArticle

Abstract

Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors and 8 rhabdomyosarcomas. Whole genome copy number and whole exome mutational profiling of multiple regions per tumor was performed followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared to clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; p=0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, while in Wilms tumor they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, while others grow worse over time.

Details

Authors
Organisations
External organisations
  • University Medical Center Groningen
  • University of Groningen
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
  • Pediatrics
Original languageEnglish
Pages (from-to)1512-1523
Number of pages12
JournalCancer Research
Volume80
Issue number7
Early online date2020 Feb 10
Publication statusPublished - 2020 Apr
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

Copyright ©2020, American Association for Cancer Research.