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 and Jason M Shohet

PLOS ONE, 2013, vol. 8, issue 11, 1-11

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

Date: 2013
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0079843

DOI: 10.1371/journal.pone.0079843

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