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A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma

Author

Listed:
  • Eveline Barbieri
  • Katleen De Preter
  • Mario Capasso
  • Peter Johansson
  • Tsz-Kwong Man
  • Zaowen Chen
  • Paris Stowers
  • Gian Paolo Tonini
  • Frank Speleman
  • Jason M Shohet

Abstract

Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p

Suggested Citation

  • Eveline Barbieri & Katleen De Preter & Mario Capasso & Peter Johansson & Tsz-Kwong Man & Zaowen Chen & Paris Stowers & Gian Paolo Tonini & Frank Speleman & Jason M Shohet, 2013. "A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-11, November.
    • Handle: RePEc:plo:pone00:0079843
    DOI: 10.1371/journal.pone.0079843
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