title: A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma.
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<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.
authors.affiliation: Texas Children's Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Eveline
authors.initials: E
authors.lastname: Barbieri
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.affiliation: CEINGE Biotecnologie Avanzate, Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Johansson
authors.affiliation: Texas Children's Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Tsz-Kwong
authors.initials: TK
authors.lastname: Man
authors.affiliation: Texas Children's Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Zaowen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Texas Children's Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Paris
authors.initials: P
authors.lastname: Stowers
authors.affiliation: Pediatric Research Institute, University of Padua, Padua, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Texas Children's Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Shohet
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2