Document Detail


The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients: correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform.
MedLine Citation:
PMID:  22904680     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The p53 gene is rarely mutated in neuroblastoma, but codon 72 polymorphism that modulates its proapoptotic activity might influence cancer risk and clinical outcome. We investigated whether this polymorphism affects neuroblastoma risk and disease outcome and assessed the biologic effects of the p53-72R and p53-72P isoforms in p53-null cells. Comparison of 288 healthy subjects and 286 neuroblastoma patients revealed that the p53-72 polymorphism had no significant impact on the risk of developing neuroblastoma; however, patients with the Pro/Pro genotype had a shorter survival than those with the Arg/Arg or the Arg/Pro genotypes even in the stage 3 and 4 subgroup without MYCN amplification. By Cox regression analysis, the p53 Pro/Pro genotype seems to be an independent marker of poor prognosis (hazard ratio = 2.74; 95% confidence interval = 1.14-6.55, P = .014) together with clinical stage, MYCN status, and age at diagnosis. In vitro, p53-72P was less effective than p53-72R in inducing apoptosis and inhibiting survival of p53-null LAN-1 cells treated with etoposide, topotecan, or ionizing radiation but not taxol. By contrast, p53-72P was more effective in promoting p21-dependent accelerated senescence, alone or in the presence of etoposide. Thus, the p53-72 Pro/Pro genotype might be a marker of poor outcome independent of MYCN amplification, possibly improving risk stratification. Moreover, the lower apoptosis and the enhanced accelerated senescence by the p53-72P isoform in response to DNA damage suggest that patients with neuroblastoma with the p53-72 Pro/Pro genotype may benefit from therapeutic protocols that do not rely only on cytotoxic drugs that function, in part, through p53 activation.
Authors:
Sara Cattelani; Giovanna Ferrari-Amorotti; Sara Galavotti; Raffaella Defferrari; Barbara Tanno; Samantha Cialfi; Jenny Vergalli; Valentina Fragliasso; Clara Guerzoni; Gloria Manzotti; Angela Rachele Soliera; Chiara Menin; Roberta Bertorelle; Heather P McDowell; Alessandro Inserra; Maria Luisa Belli; Luigi Varesio; Deborah Tweddle; Gian Paolo Tonini; Pierluigi Altavista; Carlo Dominici; Giuseppe Raschellà; Bruno Calabretta
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  14     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2013-03-18     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  634-43     Citation Subset:  IM    
Affiliation:
Department of Medical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aging / genetics
Apoptosis / genetics
Cell Line, Tumor
Child, Preschool
Codon*
Female
Gene Expression Regulation, Neoplastic
Genotype*
Humans
Infant
Infant, Newborn
Male
Middle Aged
Neoplasm Staging
Neuroblastoma / genetics*,  mortality,  pathology
Polymorphism, Single Nucleotide
Prognosis
Protein Isoforms / genetics
RNA Interference
Tumor Suppressor Protein p53 / genetics*,  metabolism
Chemical
Reg. No./Substance:
0/Codon; 0/Protein Isoforms; 0/Tumor Suppressor Protein p53
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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