<i>TP53</i> Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy
Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated <i>TP53</i> somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with seco...
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MDPI AG
2020-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2049 |
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| author | Francesco Graziano Nicholas W. Fischer Irene Bagaloni Maria Di Bartolomeo Sara Lonardi Bruno Vincenzi Giuseppe Perrone Lorenzo Fornaro Elena Ongaro Giuseppe Aprile Renato Bisonni Michele Prisciandaro David Malkin Jean Gariépy Matteo Fassan Fotios Loupakis Donatella Sarti Michela Del Prete Vincenzo Catalano Paolo Alessandroni Mauro Magnani Annamaria Ruzzo |
| author_facet | Francesco Graziano Nicholas W. Fischer Irene Bagaloni Maria Di Bartolomeo Sara Lonardi Bruno Vincenzi Giuseppe Perrone Lorenzo Fornaro Elena Ongaro Giuseppe Aprile Renato Bisonni Michele Prisciandaro David Malkin Jean Gariépy Matteo Fassan Fotios Loupakis Donatella Sarti Michela Del Prete Vincenzo Catalano Paolo Alessandroni Mauro Magnani Annamaria Ruzzo |
| author_sort | Francesco Graziano |
| collection | DOAJ |
| description | Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated <i>TP53</i> somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with second-line Ramucirumab/Paclitaxel and 62 patients who received first-line chemotherapy with Cisplatin or Oxaliplatin plus 5-Fluorouracil. Missense mutations were classified by tumor protein p53 (<i>TP53</i>) mutant-specific residual transcriptional activity scores (<i>TP53</i><sub>RTAS</sub>) and used to stratify patients into two groups: transcriptionally <i>TP53</i><sub>Active</sub> and <i>TP53</i><sub>Inactive</sub>. The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGF receptor 2 (VEGFR2) expression levels in relation to the <i>TP53</i><sub>RTAS</sub>. In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had <i>TP53</i> mutations. Ten patients with <i>TP53</i><sub>Inactive</sub> mutations showed better OS than carriers of other <i>TP53</i> mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17–0.85, <i>p</i> = 0.02). In the chemotherapy group, 41/62 (66%) patients had <i>TP53</i> mutations, and the 11 carriers of <i>TP53</i><sub>Inactive</sub> mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17–5.95, <i>p</i> = 0.02). VEGF-A mRNA expression levels were significantly increased in <i>TP53</i><sub>Inactive</sub> cases. Further studies are warranted to explore the effect of <i>TP53</i><sub>Inactive</sub> mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease. |
| first_indexed | 2024-03-10T18:13:42Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T18:13:42Z |
| publishDate | 2020-07-01 |
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| series | Cancers |
| spelling | doaj.art-1df20b8f3dfd424b9370a0c9d03d32452023-11-20T07:54:07ZengMDPI AGCancers2072-66942020-07-01128204910.3390/cancers12082049<i>TP53</i> Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard ChemotherapyFrancesco Graziano0Nicholas W. Fischer1Irene Bagaloni2Maria Di Bartolomeo3Sara Lonardi4Bruno Vincenzi5Giuseppe Perrone6Lorenzo Fornaro7Elena Ongaro8Giuseppe Aprile9Renato Bisonni10Michele Prisciandaro11David Malkin12Jean Gariépy13Matteo Fassan14Fotios Loupakis15Donatella Sarti16Michela Del Prete17Vincenzo Catalano18Paolo Alessandroni19Mauro Magnani20Annamaria Ruzzo21Medical Oncology Unit, Azienda, Ospedali Riuniti Marche Nord, 61121 Pesaro, ItalyGenetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, CanadaDepartment of Biomolecular Sciences, Università degli Studi di Urbino, 61032 Fano, ItalyDepartment of Medical Oncology, Istituto Nazionale dei Tumori di Milano, 20133 Milan, ItalyVeneto Institute of Oncology IOV–IRCCS, 35128 Padova, ItalyDepartment of Oncology, Campus Bio-Medico University, 00128 Rome, ItalyDepartment of Oncology, Campus Bio-Medico University, 00128 Rome, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyDepartment of Oncology, University and General Hospital, 33100 Udine, ItalyDepartment of Oncology, San Bortolo General Hospital, 36100 Vicenza, ItalyMedical Oncology Unit, Hospital of Fermo, 63900 Fermo, ItalyDepartment of Medical Oncology, Istituto Nazionale dei Tumori di Milano, 20133 Milan, ItalyGenetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, CanadaVeneto Institute of Oncology IOV–IRCCS, 35128 Padova, ItalyVeneto Institute of Oncology IOV–IRCCS, 35128 Padova, ItalyMedical Oncology Unit, Azienda, Ospedali Riuniti Marche Nord, 61121 Pesaro, ItalyMedical Oncology Unit, Hospital of Fermo, 63900 Fermo, ItalyMedical Oncology Unit, Azienda, Ospedali Riuniti Marche Nord, 61121 Pesaro, ItalyMedical Oncology Unit, Azienda, Ospedali Riuniti Marche Nord, 61121 Pesaro, ItalyDepartment of Biomolecular Sciences, Università degli Studi di Urbino, 61032 Fano, ItalyDepartment of Biomolecular Sciences, Università degli Studi di Urbino, 61032 Fano, ItalyLoss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated <i>TP53</i> somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with second-line Ramucirumab/Paclitaxel and 62 patients who received first-line chemotherapy with Cisplatin or Oxaliplatin plus 5-Fluorouracil. Missense mutations were classified by tumor protein p53 (<i>TP53</i>) mutant-specific residual transcriptional activity scores (<i>TP53</i><sub>RTAS</sub>) and used to stratify patients into two groups: transcriptionally <i>TP53</i><sub>Active</sub> and <i>TP53</i><sub>Inactive</sub>. The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGF receptor 2 (VEGFR2) expression levels in relation to the <i>TP53</i><sub>RTAS</sub>. In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had <i>TP53</i> mutations. Ten patients with <i>TP53</i><sub>Inactive</sub> mutations showed better OS than carriers of other <i>TP53</i> mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17–0.85, <i>p</i> = 0.02). In the chemotherapy group, 41/62 (66%) patients had <i>TP53</i> mutations, and the 11 carriers of <i>TP53</i><sub>Inactive</sub> mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17–5.95, <i>p</i> = 0.02). VEGF-A mRNA expression levels were significantly increased in <i>TP53</i><sub>Inactive</sub> cases. Further studies are warranted to explore the effect of <i>TP53</i><sub>Inactive</sub> mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.https://www.mdpi.com/2072-6694/12/8/2049gastric cancer<i>TP53</i>RamucirumabPaclitaxelangiogenesis |
| spellingShingle | Francesco Graziano Nicholas W. Fischer Irene Bagaloni Maria Di Bartolomeo Sara Lonardi Bruno Vincenzi Giuseppe Perrone Lorenzo Fornaro Elena Ongaro Giuseppe Aprile Renato Bisonni Michele Prisciandaro David Malkin Jean Gariépy Matteo Fassan Fotios Loupakis Donatella Sarti Michela Del Prete Vincenzo Catalano Paolo Alessandroni Mauro Magnani Annamaria Ruzzo <i>TP53</i> Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy Cancers gastric cancer <i>TP53</i> Ramucirumab Paclitaxel angiogenesis |
| title | <i>TP53</i> Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy |
| title_full | <i>TP53</i> Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy |
| title_fullStr | <i>TP53</i> Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy |
| title_full_unstemmed | <i>TP53</i> Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy |
| title_short | <i>TP53</i> Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy |
| title_sort | i tp53 i mutation analysis in gastric cancer and clinical outcomes of patients with metastatic disease treated with ramucirumab paclitaxel or standard chemotherapy |
| topic | gastric cancer <i>TP53</i> Ramucirumab Paclitaxel angiogenesis |
| url | https://www.mdpi.com/2072-6694/12/8/2049 |
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