The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients: correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform.
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.
Department of Medical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Sara
S
Cattelani
Giovanna
G
Ferrari-Amorotti
Sara
S
Galavotti
Raffaella
R
Defferrari
Barbara
B
Tanno
Samantha
S
Cialfi
Jenny
J
Vergalli
Valentina
V
Fragliasso
Clara
C
Guerzoni
Gloria
G
Manzotti
Angela Rachele
AR
Soliera
Chiara
C
Menin
Roberta
R
Bertorelle
Heather P
HP
McDowell
Alessandro
A
Inserra
Maria Luisa
ML
Belli
Luigi
L
Varesio
Deborah
D
Tweddle
Gian Paolo
GP
Tonini
Pierluigi
P
Altavista
Carlo
C
Dominici
Giuseppe
G
Raschellà
Bruno
B
Calabretta
D000328:Adult; D000375:Aging / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002675:Child, Preschool; D003062:Codon; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D003062:Codon; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53