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

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 MD...

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Autores principales: Barbieri, Eveline, De Preter, Katleen, Capasso, Mario, Johansson, Peter, Man, Tsz-Kwong, Chen, Zaowen, Stowers, Paris, Tonini, Gian Paolo, Speleman, Frank, Shohet, Jason M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865347/
https://www.ncbi.nlm.nih.gov/pubmed/24348903
http://dx.doi.org/10.1371/journal.pone.0079843
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author Barbieri, Eveline
De Preter, Katleen
Capasso, Mario
Johansson, Peter
Man, Tsz-Kwong
Chen, Zaowen
Stowers, Paris
Tonini, Gian Paolo
Speleman, Frank
Shohet, Jason M.
author_facet Barbieri, Eveline
De Preter, Katleen
Capasso, Mario
Johansson, Peter
Man, Tsz-Kwong
Chen, Zaowen
Stowers, Paris
Tonini, Gian Paolo
Speleman, Frank
Shohet, Jason M.
author_sort Barbieri, Eveline
collection PubMed
description 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<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.
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spelling pubmed-38653472013-12-17 A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma Barbieri, Eveline De Preter, Katleen Capasso, Mario Johansson, Peter Man, Tsz-Kwong Chen, Zaowen Stowers, Paris Tonini, Gian Paolo Speleman, Frank Shohet, Jason M. PLoS One Research Article 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<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma. Public Library of Science 2013-11-19 /pmc/articles/PMC3865347/ /pubmed/24348903 http://dx.doi.org/10.1371/journal.pone.0079843 Text en © 2013 Barbieri et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Barbieri, Eveline
De Preter, Katleen
Capasso, Mario
Johansson, Peter
Man, Tsz-Kwong
Chen, Zaowen
Stowers, Paris
Tonini, Gian Paolo
Speleman, Frank
Shohet, Jason M.
A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma
title A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma
title_full A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma
title_fullStr A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma
title_full_unstemmed A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma
title_short A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma
title_sort p53 drug response signature identifies prognostic genes in high-risk neuroblastoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865347/
https://www.ncbi.nlm.nih.gov/pubmed/24348903
http://dx.doi.org/10.1371/journal.pone.0079843
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