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Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer

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, t...

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Autores principales: Pallocca, Matteo, Goeman, Frauke, De Nicola, Francesca, Melucci, Elisa, Sperati, Francesca, Terrenato, Irene, Pizzuti, Laura, Casini, Beatrice, Gallo, Enzo, Amoreo, Carla Azzurra, Vici, Patrizia, Di Lauro, Luigi, Buglioni, Simonetta, Diodoro, Maria Grazia, Pescarmona, Edoardo, Mazzotta, Marco, Barba, Maddalena, Fanciulli, Maurizio, De Maria, Ruggero, Ciliberto, Gennaro, Maugeri-Saccà, Marcello
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122687/
https://www.ncbi.nlm.nih.gov/pubmed/30180862
http://dx.doi.org/10.1186/s12967-018-1607-3
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author Pallocca, Matteo
Goeman, Frauke
De Nicola, Francesca
Melucci, Elisa
Sperati, Francesca
Terrenato, Irene
Pizzuti, Laura
Casini, Beatrice
Gallo, Enzo
Amoreo, Carla Azzurra
Vici, Patrizia
Di Lauro, Luigi
Buglioni, Simonetta
Diodoro, Maria Grazia
Pescarmona, Edoardo
Mazzotta, Marco
Barba, Maddalena
Fanciulli, Maurizio
De Maria, Ruggero
Ciliberto, Gennaro
Maugeri-Saccà, Marcello
author_facet Pallocca, Matteo
Goeman, Frauke
De Nicola, Francesca
Melucci, Elisa
Sperati, Francesca
Terrenato, Irene
Pizzuti, Laura
Casini, Beatrice
Gallo, Enzo
Amoreo, Carla Azzurra
Vici, Patrizia
Di Lauro, Luigi
Buglioni, Simonetta
Diodoro, Maria Grazia
Pescarmona, Edoardo
Mazzotta, Marco
Barba, Maddalena
Fanciulli, Maurizio
De Maria, Ruggero
Ciliberto, Gennaro
Maugeri-Saccà, Marcello
author_sort Pallocca, Matteo
collection PubMed
description 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+/TP53(mut(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+/TP53(mut(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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1607-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-61226872018-09-10 Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer Pallocca, Matteo Goeman, Frauke De Nicola, Francesca Melucci, Elisa Sperati, Francesca Terrenato, Irene Pizzuti, Laura Casini, Beatrice Gallo, Enzo Amoreo, Carla Azzurra Vici, Patrizia Di Lauro, Luigi Buglioni, Simonetta Diodoro, Maria Grazia Pescarmona, Edoardo Mazzotta, Marco Barba, Maddalena Fanciulli, Maurizio De Maria, Ruggero Ciliberto, Gennaro Maugeri-Saccà, Marcello J Transl Med Commentary 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+/TP53(mut(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+/TP53(mut(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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1607-3) contains supplementary material, which is available to authorized users. BioMed Central 2018-09-04 /pmc/articles/PMC6122687/ /pubmed/30180862 http://dx.doi.org/10.1186/s12967-018-1607-3 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Commentary
Pallocca, Matteo
Goeman, Frauke
De Nicola, Francesca
Melucci, Elisa
Sperati, Francesca
Terrenato, Irene
Pizzuti, Laura
Casini, Beatrice
Gallo, Enzo
Amoreo, Carla Azzurra
Vici, Patrizia
Di Lauro, Luigi
Buglioni, Simonetta
Diodoro, Maria Grazia
Pescarmona, Edoardo
Mazzotta, Marco
Barba, Maddalena
Fanciulli, Maurizio
De Maria, Ruggero
Ciliberto, Gennaro
Maugeri-Saccà, Marcello
Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer
title 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_short 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
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122687/
https://www.ncbi.nlm.nih.gov/pubmed/30180862
http://dx.doi.org/10.1186/s12967-018-1607-3
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