Divergent clonal selection dominates medulloblastoma at recurrence

Academic Article

Abstract

  • © 2016 Macmillan Publishers Limited. All rights reserved. The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
  • Authors

    Published In

  • Nature  Journal
  • Digital Object Identifier (doi)

    Author List

  • Morrissy AS; Garzia L; Shih DJH; Zuyderduyn S; Huang X; Skowron P; Remke M; Cavalli FMG; Ramaswamy V; Lindsay PE
  • Start Page

  • 351
  • End Page

  • 357
  • Volume

  • 529
  • Issue

  • 7586