TY - JOUR
T1 - The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients
T2 - Correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform
AU - Cattelani, Sara
AU - Ferrari-Amorotti, Giovanna
AU - Galavotti, Sara
AU - Defferrari, Raffaella
AU - Tanno, Barbara
AU - Cialfi, Samantha
AU - Vergalli, Jenny
AU - Fragliasso, Valentina
AU - Guerzoni, Clara
AU - Manzotti, Gloria
AU - Soliera, Angela Rachele
AU - Menin, Chiara
AU - Bertorelle, Roberta
AU - McDowell, Heather P.
AU - Inserra, Alessandro
AU - Belli, Maria Luisa
AU - Varesio, Luigi
AU - Tweddle, Deborah
AU - Tonini, Gian Paolo
AU - Altavista, Pierluigi
AU - Dominici, Carlo
AU - Raschellà, Giuseppe
AU - Calabretta, Bruno
PY - 2012/7
Y1 - 2012/7
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.12594
DO - 10.1593/neo.12594
M3 - Article
C2 - 22904680
AN - SCOPUS:84865631011
VL - 14
SP - 634
EP - 643
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 7
ER -