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Increased Frequency of Aberrations in the p53/MDM2/p14^ARF Pathway in Neuroblastoma Cell Lines Established at Relapse

¹ Northern Institute for Cancer Research, University of Newcastle Upon Tyne, United Kingdom; ² University of Western Australia, Perth, Australia; and ³ Vysis, Inc., Downers Grove, Illinois

Requests for reprints: Deborah Tweddle, Northern Institute for Cancer Research, Paul O'Gorman Building, Framlington Place, University of Newcastle, Newcastle upon Tyne, NE2 4HH, United Kingdom. Phone: 44-191-246-4421; Fax: 44-191-246-4301; E-mail: d.a.tweddle{at}ncl.ac.uk.

p53 mutations have been reported in cell lines derived from relapsed neuroblastoma tumors. We hypothesize that functional inactivation of p53 by mutation or other mechanisms is common in relapsed neuroblastoma and can contribute to chemoresistance. Our aim was to determine the frequency of p53 mutations, p14^ARF methylation, or deletion and MDM2 amplification in 23 neuroblastoma cell lines (6 derived at diagnosis and 17 derived at relapse). One cell line was p53 mutant (BE2c) and two cell lines were deleted for p14^ARF (LAN-6 and SHEP). Two cell lines were methylated for p14^ARF (GIMEN and PER-108), one of which had low levels of p14^ARF mRNA expression which increased following demethylation with 5-aza-2/deoxycytidine treatment (GIMEN), and four cell lines were confirmed to be MDM2-amplified. All these cell lines were derived from neuroblastomas at relapse. Inactivation of the p53 pathway was observed in 9 out of 17 neuroblastoma cell lines (53%) established at relapse and in none of the cell lines established from pretreatment tumors. If these data are confirmed in neuroblastoma tumors, this suggests that p53-independent therapy and reactivation of inactive p53 approaches would be useful in the management of relapsed neuroblastoma. (Cancer Res 2006; 66(4): 2138-45)

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