High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma.
OBJECTIVE
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/p14(ARF) pathway in 9 of 17 (53%) neuroblastoma cell lines established at relapse.


OBJECTIVE
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, p14(ARF) 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 p14(ARF) inactivation in 12 of 41 (29%) cases: 3 had p14(ARF) 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.
Department of Cellular Pathology, Northern Institute for Cancer Research, Royal Victoria Infirmary, Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom.
Jane
J
Carr-Wilkinson
Kieran
K
O'Toole
Katrina M
KM
Wood
Christine C
CC
Challen
Angela G
AG
Baker
Julian R
JR
Board
Laura
L
Evans
Michael
M
Cole
Nai-Kong V
NK
Cheung
Joachim
J
Boos
Gabriele
G
Köhler
Ivo
I
Leuschner
Andrew D J
AD
Pearson
John
J
Lunec
Deborah A
DA
Tweddle
D019175:DNA Methylation; D005784:Gene Amplification; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012008:Recurrence; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism
D025803:Tumor Suppressor Protein p14ARF; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2