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-...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-07-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558612800972 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sara Cattelani |
| collection | DOAJ |
| description | 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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| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-a82fdf1e4a494fedb36b4d5a5686f82e2022-12-22T02:47:07ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-07-0114763464310.1593/neo.12594The p53 Codon 72 Pro/Pro Genotype Identifies Poor-Prognosis Neuroblastoma Patients: Correlation with Reduced Apoptosis and Enhanced Senescence by the p53-72P IsoformSara Cattelani0Giovanna Ferrari-Amorotti1Sara Galavotti2Raffaella Defferrari3Barbara Tanno4Samantha Cialfi5Jenny Vergalli6Valentina Fragliasso7Clara Guerzoni8Gloria Manzotti9Angela Rachele Soliera10Chiara Menin11Roberta Bertorelle12Heather P. McDowell13Alessandro Inserra14Maria Luisa Belli15Luigi Varesio16Deborah Tweddle17Gian Paolo Tonini18Pierluigi Altavista19Carlo Dominici20Giuseppe Raschellà21Bruno Calabretta22Department of Medical Sciences, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Medical Sciences, University of Modena and Reggio Emilia, Modena, ItalySamantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, United KingdomFondazione Italiana per la Lotta al Neuroblastoma, G. Gaslini Institute, Genoa, ItalyUnit of Radiation Biology and Human Health, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Research Center Casaccia, Rome, ItalyDepartment of Pediatrics, Sapienza University, Rome, ItalyDepartment of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PADepartment of Medical Sciences, University of Modena and Reggio Emilia, Modena, ItalyLaboratory of Oncology Research, Istituto Ortopedico Rizzoli, Bologna, ItalyDepartment of Medical Sciences, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Medical Sciences, University of Modena and Reggio Emilia, Modena, ItalyMolecular Immunology and Diagnostic Oncology, Istituto Oncologico Veneto, IRCCS, Padova, ItalyMolecular Immunology and Diagnostic Oncology, Istituto Oncologico Veneto, IRCCS, Padova, ItalyDepartment of Oncology, Alder Hey Children’s NHS Foundation Trust, Liverpool, United KingdomDivision of Surgery, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyDepartment of Hematology-Oncology, G. Gaslini Institute, Genoa, ItalyLaboratory of Molecular Biology, G. Gaslini Institute, Genoa, ItalyFondazione Italiana per la Lotta al Neuroblastoma, G. Gaslini Institute, Genoa, ItalyUnit of Radiation Biology and Human Health, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Research Center Casaccia, Rome, ItalyUnit of Radiation Biology and Human Health, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Research Center Casaccia, Rome, ItalyDepartment of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PAUnit of Radiation Biology and Human Health, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Research Center Casaccia, Rome, ItalyDepartment of Medical Sciences, University of Modena and Reggio Emilia, Modena, ItalyThe 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.http://www.sciencedirect.com/science/article/pii/S1476558612800972 |
| spellingShingle | 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 The p53 Codon 72 Pro/Pro Genotype Identifies Poor-Prognosis Neuroblastoma Patients: Correlation with Reduced Apoptosis and Enhanced Senescence by the p53-72P Isoform Neoplasia: An International Journal for Oncology Research |
| title | The p53 Codon 72 Pro/Pro Genotype Identifies Poor-Prognosis Neuroblastoma Patients: Correlation with Reduced Apoptosis and Enhanced Senescence by the p53-72P Isoform |
| title_full | The p53 Codon 72 Pro/Pro Genotype Identifies Poor-Prognosis Neuroblastoma Patients: Correlation with Reduced Apoptosis and Enhanced Senescence by the p53-72P Isoform |
| title_fullStr | The p53 Codon 72 Pro/Pro Genotype Identifies Poor-Prognosis Neuroblastoma Patients: Correlation with Reduced Apoptosis and Enhanced Senescence by the p53-72P Isoform |
| title_full_unstemmed | The p53 Codon 72 Pro/Pro Genotype Identifies Poor-Prognosis Neuroblastoma Patients: Correlation with Reduced Apoptosis and Enhanced Senescence by the p53-72P Isoform |
| title_short | The p53 Codon 72 Pro/Pro Genotype Identifies Poor-Prognosis Neuroblastoma Patients: Correlation with Reduced Apoptosis and Enhanced Senescence by the p53-72P Isoform |
| title_sort | p53 codon 72 pro pro genotype identifies poor prognosis neuroblastoma patients correlation with reduced apoptosis and enhanced senescence by the p53 72p isoform |
| url | http://www.sciencedirect.com/science/article/pii/S1476558612800972 |
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