Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer
Abstract We have previously reported that nuclear expression of the Hippo transducer TAZ in association with Wnt pathway mutations negatively impacts survival outcomes in advanced gastric cancer (GC) patients. Here, we extended these previous findings by investigating another oncogenic cooperation,...
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| Format: | Article |
| Language: | English |
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BioMed Central
2018-09-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s12967-018-1607-3 |
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doaj-art-86f47c25616445ca9ed68f0ca5d505c42018-09-09T11:13:40ZengBioMed CentralJournal of Translational Medicine1479-58762018-09-011611610.1186/s12967-018-1607-3Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancerMatteo Pallocca0Frauke Goeman1Francesca De Nicola2Elisa Melucci3Francesca Sperati4Irene Terrenato5Laura Pizzuti6Beatrice Casini7Enzo Gallo8Carla Azzurra Amoreo9Patrizia Vici10Luigi Di Lauro11Simonetta Buglioni12Maria Grazia Diodoro13Edoardo Pescarmona14Marco Mazzotta15Maddalena Barba16Maurizio Fanciulli17Ruggero De Maria18Gennaro Ciliberto19Marcello Maugeri-Saccà20SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS “Regina Elena” National Cancer InstituteOncogenomic and Epigenetic Unit, IRCCS “Regina Elena” National Cancer InstituteSAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS “Regina Elena” National Cancer InstituteDepartment of Pathology, IRCCS “Regina Elena” National Cancer InstituteBiostatistics-Scientific Direction, IRCCS “Regina Elena” National Cancer InstituteBiostatistics-Scientific Direction, IRCCS “Regina Elena” National Cancer InstituteDivision of Medical Oncology 2, IRCCS “Regina Elena” National Cancer InstituteDepartment of Pathology, IRCCS “Regina Elena” National Cancer InstituteDepartment of Pathology, IRCCS “Regina Elena” National Cancer InstituteDepartment of Pathology, IRCCS “Regina Elena” National Cancer InstituteDivision of Medical Oncology 2, IRCCS “Regina Elena” National Cancer InstituteDivision of Medical Oncology 2, IRCCS “Regina Elena” National Cancer InstituteDepartment of Pathology, IRCCS “Regina Elena” National Cancer InstituteDepartment of Pathology, IRCCS “Regina Elena” National Cancer InstituteDepartment of Pathology, IRCCS “Regina Elena” National Cancer InstituteMedical Oncology Unit, Policlinico Sant’AndreaDivision of Medical Oncology 2, IRCCS “Regina Elena” National Cancer InstituteSAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS “Regina Elena” National Cancer InstituteInstitute of General Pathology, Catholic University of the Sacred Heart and Fondazione Policlinico Universitario Agostino GemelliScientific Direction, IRCCS “Regina Elena” National Cancer InstituteDivision of Medical Oncology 2, IRCCS “Regina Elena” National Cancer InstituteAbstract We have previously reported that nuclear expression of the Hippo transducer TAZ in association with Wnt pathway mutations negatively impacts survival outcomes in advanced gastric cancer (GC) patients. Here, we extended these previous findings by investigating another oncogenic cooperation, namely, the interplay between YAP, the TAZ paralogue, and p53. The molecular output of the YAP-p53 cooperation is dependent on TP53 mutational status. In the absence of mutations, the YAP-p53 crosstalk elicits a pro-apoptotic response, whereas in the presence of TP53 mutations it activates a pro-proliferative transcriptional program. In order to study this phenomenon, we re-analyzed data from 83 advanced GC patients treated with chemotherapy whose tissue samples had been characterized for YAP expression (immunohistochemistry, IHC) and TP53 mutations (deep sequencing). In doing so, we generated a molecular model combining nuclear YAP expression in association with TP53 missense variants (YAP+/TP53mut(mv)). Surprisingly, this signature was associated with a decreased risk of disease progression (multivariate Cox for progression-free survival: HR 0.53, 95% CI 0.30–0.91, p = 0.022). The YAP+/TP53mut(mv) model was also associated with better OS in the subgroup of patients who received chemotherapy beyond the first-line setting (multivariate Cox: HR 0.36, 95% CI 0.16–0.81, p = 0.013). Collectively, our findings suggest that the oncogenic cooperation between YAP and mutant p53 may translate into better survival outcomes. This apparent paradox can be explained by the pro-proliferative program triggered by YAP and mutant p53, that supposedly renders cancer cells more vulnerable to cytotoxic therapies.http://link.springer.com/article/10.1186/s12967-018-1607-3Gastric cancerHippo pathwayYAPTP53 mutations |
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| language |
English |
| format |
Article |
| author |
Matteo Pallocca Frauke Goeman Francesca De Nicola Elisa Melucci Francesca Sperati Irene Terrenato Laura Pizzuti Beatrice Casini Enzo Gallo Carla Azzurra Amoreo Patrizia Vici Luigi Di Lauro Simonetta Buglioni Maria Grazia Diodoro Edoardo Pescarmona Marco Mazzotta Maddalena Barba Maurizio Fanciulli Ruggero De Maria Gennaro Ciliberto Marcello Maugeri-Saccà |
| spellingShingle |
Matteo Pallocca Frauke Goeman Francesca De Nicola Elisa Melucci Francesca Sperati Irene Terrenato Laura Pizzuti Beatrice Casini Enzo Gallo Carla Azzurra Amoreo Patrizia Vici Luigi Di Lauro Simonetta Buglioni Maria Grazia Diodoro Edoardo Pescarmona Marco Mazzotta Maddalena Barba Maurizio Fanciulli Ruggero De Maria Gennaro Ciliberto Marcello Maugeri-Saccà Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer Journal of Translational Medicine Gastric cancer Hippo pathway YAP TP53 mutations |
| author_facet |
Matteo Pallocca Frauke Goeman Francesca De Nicola Elisa Melucci Francesca Sperati Irene Terrenato Laura Pizzuti Beatrice Casini Enzo Gallo Carla Azzurra Amoreo Patrizia Vici Luigi Di Lauro Simonetta Buglioni Maria Grazia Diodoro Edoardo Pescarmona Marco Mazzotta Maddalena Barba Maurizio Fanciulli Ruggero De Maria Gennaro Ciliberto Marcello Maugeri-Saccà |
| author_sort |
Matteo Pallocca |
| title |
Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer |
| title_short |
Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer |
| title_full |
Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer |
| title_fullStr |
Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer |
| title_full_unstemmed |
Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer |
| title_sort |
coexisting yap expression and tp53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer |
| publisher |
BioMed Central |
| series |
Journal of Translational Medicine |
| issn |
1479-5876 |
| publishDate |
2018-09-01 |
| description |
Abstract We have previously reported that nuclear expression of the Hippo transducer TAZ in association with Wnt pathway mutations negatively impacts survival outcomes in advanced gastric cancer (GC) patients. Here, we extended these previous findings by investigating another oncogenic cooperation, namely, the interplay between YAP, the TAZ paralogue, and p53. The molecular output of the YAP-p53 cooperation is dependent on TP53 mutational status. In the absence of mutations, the YAP-p53 crosstalk elicits a pro-apoptotic response, whereas in the presence of TP53 mutations it activates a pro-proliferative transcriptional program. In order to study this phenomenon, we re-analyzed data from 83 advanced GC patients treated with chemotherapy whose tissue samples had been characterized for YAP expression (immunohistochemistry, IHC) and TP53 mutations (deep sequencing). In doing so, we generated a molecular model combining nuclear YAP expression in association with TP53 missense variants (YAP+/TP53mut(mv)). Surprisingly, this signature was associated with a decreased risk of disease progression (multivariate Cox for progression-free survival: HR 0.53, 95% CI 0.30–0.91, p = 0.022). The YAP+/TP53mut(mv) model was also associated with better OS in the subgroup of patients who received chemotherapy beyond the first-line setting (multivariate Cox: HR 0.36, 95% CI 0.16–0.81, p = 0.013). Collectively, our findings suggest that the oncogenic cooperation between YAP and mutant p53 may translate into better survival outcomes. This apparent paradox can be explained by the pro-proliferative program triggered by YAP and mutant p53, that supposedly renders cancer cells more vulnerable to cytotoxic therapies. |
| topic |
Gastric cancer Hippo pathway YAP TP53 mutations |
| url |
http://link.springer.com/article/10.1186/s12967-018-1607-3 |
| _version_ |
1612610014928699392 |