High frequency of p53/MDM2/p14ARF pathway abnormalities in relapsed neuroblastoma Journal Article


Authors: Carr-Wilkinson, J.; O'Toole, K.; Wood, K. M.; Challen, C. C.; Baker, A. G.; Board, J. R.; Evans, L.; Cole, M.; Cheung, N. K. V.; Boos, J.; Köhler, G.; Leuschner, I.; Pearson, A. D. J.; Lunec, J.; Tweddle, D. A.
Article Title: High frequency of p53/MDM2/p14ARF pathway abnormalities in relapsed neuroblastoma
Abstract: Purpose: Most neuroblastomas initially respond to therapy but many relapse with chemoresistant disease. p53 mutations are rare in diagnostic neuroblastomas, but we have previously reported inactivation of the p53/MDM2/p14ARF pathway in 9 of 17 (53%) neuroblastoma cell lines established at relapse. Hypothesis: Inactivation of the p53/MDM2/p14 ARF pathway develops during treatment and contributes to neuroblastoma relapse. Methods: Eighty-four neuroblastomas were studied from 41 patients with relapsed neuroblastoma including 38 paired neuroblastomas at different stages of therapy. p53 mutations were detected by automated sequencing, p14ARF methylation and deletion by methylation-specific PCR and duplex PCR, respectively, and MDM2 amplification by fluorescent in situ hybridization. Results: Abnormalities in the p53 pathway were identified in 20 of 41 (49%) cases. Downstream defects due to inactivating missense p53 mutations were identified in 6 of 41 (15%) cases, 5 following chemotherapy and/or at relapse and 1 at diagnosis, postchemotherapy, and relapse. The presence of a p53 mutation was independently prognostic for overall survival (hazard ratio, 3.4; 95% confidence interval, 1.2-9.9; P = 0.02). Upstream defects were present in 35% of cases: MDM2 amplification in 3 cases, all at diagnosis and relapse and p14ARF inactivation in 12 of 41 (29%) cases: 3 had p14ARF methylation, 2 after chemotherapy, and 9 had homozygous deletions, 8 at diagnosis and relapse. Conclusions: These results show that a high proportion of neuroblastomas which relapse have an abnormality in the p53 pathway. The majority have upstream defects suggesting that agents which reactivate wild-type p53 would be beneficial, in contrast to those with downstream defects in which p53-independent therapies are indicated. ©2010 AACR.
Keywords: adolescent; adult; cancer chemotherapy; child; clinical article; preschool child; school child; gene mutation; gene sequence; methylation; gene deletion; missense mutation; mutation; polymorphism, single nucleotide; cancer patient; cancer diagnosis; polymerase chain reaction; gene amplification; recurrence; cancer cell culture; protein p53; dna methylation; fluorescence in situ hybridization; infant; neuroblastoma; cancer relapse; tumor suppressor protein p14arf; protein p14; protein mdm2; proto-oncogene proteins c-mdm2; genes, p53
Journal Title: Clinical Cancer Research
Volume: 16
Issue: 4
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2010-02-15
Start Page: 1108
End Page: 1118
Language: English
DOI: 10.1158/1078-0432.ccr-09-1865
PUBMED: 20145180
PROVIDER: scopus
PMCID: PMC2842933
DOI/URL:
Notes: --- - "Cited By (since 1996): 4" - "Export Date: 20 April 2011" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Nai-Kong Cheung
    439 Cheung