A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma

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

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish
Article numbere79843
JournalPLoS One
Volume8
Issue number11
DOIs
Publication statusPublished - Nov 19 2013

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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