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The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients: correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform.

ABSTRACT: 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.

SUBMITTER: Cattelani S

PROVIDER: S-EPMC3421959 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients: correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform.

Cattelani Sara S Ferrari-Amorotti Giovanna G Galavotti Sara S Defferrari Raffaella R Tanno Barbara B Cialfi Samantha S Vergalli Jenny J Fragliasso Valentina V Guerzoni Clara C Manzotti Gloria G Soliera Angela Rachele AR Menin Chiara C Bertorelle Roberta R McDowell Heather P HP Inserra Alessandro A Belli Maria Luisa ML Varesio Luigi L Tweddle Deborah D Tonini Gian Paolo GP Altavista Pierluigi P Dominici Carlo C Raschellà Giuseppe G Calabretta Bruno B

Neoplasia (New York, N.Y.) 20120701 7

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 ...[more]

PMID: 22904680

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Project description:IntroductionThe absence of mutation or promoter hypermethylation in the BRCA2 gene in the majority of breast cancer cases has indicated alternative ways of its involvement, deregulated expression being one possibility. We show how a polymorphism in the 5' untranslated region (UTR) of BRCA2 can serve as one such factor. Based on the hypothesis that variants of genes involved in the same pathway can influence the risk provided for breast cancer, the status of p53 codon 72 polymorphism was also investigated and a possible interaction between the polymorphisms was examined.MethodsThe luciferase reporter assay followed by RNA secondary structure analysis was used for the functional characterization of -26 5' UTR G>A polymorphism in BRCA2. The genotype and the allele frequency for the polymorphisms were determined and relative risk adjusted for age was calculated in a case-control study of 576 individuals (243 patients and 333 controls) from north India.Results-26 G>A polymorphism in the 5' UTR of BRCA2 was found to be functional whereby the A allele increased the reporter gene expression by twice that of the G allele in MCF-7 (P = 0.003) and HeLa (P = 0.013) cells. RNA secondary structure analysis by two different programs predicted the A allele to alter the stability of a loop in the vicinity of the translation start site. Its direct implication in breast cancer became evident by a case-control study in which the heterozygous genotype was found to be protective in nature (P heterozygote advantage model = 0.0005, odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.4 to 0.8), which was further supported by trends observed in a genomic instability study. The p53 codon 72 Arg homozygous genotype was found to be over-represented in patients (P = 0.0005, OR = 2.3, 95% CI = 1.4 to 3.6). The interaction study indicated an increased protection under simultaneous presence of protector genotypes of both the polymorphic loci (P = 0.0001, OR = 0.2, 95% CI = 0.1 to 0.4).ConclusionOur study shows that -26 5' UTR polymorphism in BRCA2 can modulate the fine-tuned regulation of the multifunctional gene BRCA2 and renders risk or protection according to the genotype status in the sporadic form of breast cancer, which is further influenced by the germline genetic backgrounds of codon 72 polymorphism of p53.

Dataset Information

The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients: correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform.

Publications

The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients: correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform.

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