Cargando…

Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy

BACKGROUND: An extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by o...

Descripción completa

Detalles Bibliográficos
Autores principales: Melucci, Elisa, Casini, Beatrice, Ronchetti, Livia, Pizzuti, Laura, Sperati, Francesca, Pallocca, Matteo, De Nicola, Francesca, Goeman, Frauke, Gallo, Enzo, Amoreo, Carla Azzurra, Sergi, Domenico, Terrenato, Irene, Vici, Patrizia, Di Lauro, Luigi, Diodoro, Maria Grazia, Pescarmona, Edoardo, Barba, Maddalena, Mazzotta, Marco, Mottolese, Marcella, Fanciulli, Maurizio, Ciliberto, Gennaro, De Maria, Ruggero, Buglioni, Simonetta, 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/PMC5800016/
https://www.ncbi.nlm.nih.gov/pubmed/29402328
http://dx.doi.org/10.1186/s12967-018-1385-y
_version_ 1783298120310849536
author Melucci, Elisa
Casini, Beatrice
Ronchetti, Livia
Pizzuti, Laura
Sperati, Francesca
Pallocca, Matteo
De Nicola, Francesca
Goeman, Frauke
Gallo, Enzo
Amoreo, Carla Azzurra
Sergi, Domenico
Terrenato, Irene
Vici, Patrizia
Di Lauro, Luigi
Diodoro, Maria Grazia
Pescarmona, Edoardo
Barba, Maddalena
Mazzotta, Marco
Mottolese, Marcella
Fanciulli, Maurizio
Ciliberto, Gennaro
De Maria, Ruggero
Buglioni, Simonetta
Maugeri-Saccà, Marcello
author_facet Melucci, Elisa
Casini, Beatrice
Ronchetti, Livia
Pizzuti, Laura
Sperati, Francesca
Pallocca, Matteo
De Nicola, Francesca
Goeman, Frauke
Gallo, Enzo
Amoreo, Carla Azzurra
Sergi, Domenico
Terrenato, Irene
Vici, Patrizia
Di Lauro, Luigi
Diodoro, Maria Grazia
Pescarmona, Edoardo
Barba, Maddalena
Mazzotta, Marco
Mottolese, Marcella
Fanciulli, Maurizio
Ciliberto, Gennaro
De Maria, Ruggero
Buglioni, Simonetta
Maugeri-Saccà, Marcello
author_sort Melucci, Elisa
collection PubMed
description BACKGROUND: An extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by oncogenic mutations. On this ground, we hypothesized that YAP/TAZ- and Wnt-related biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. METHODS: In the present study, we included 86 patients with advanced GC treated with first-line chemotherapy in prospective phase II trials or in routine clinical practice. Tissue samples were immunostained to evaluate the expression of YAP/TAZ. Mutational status of key Wnt pathway genes (CTNNB1, APC and FBXW7) was assessed by targeted DNA next-generation sequencing (NGS). Survival curves were estimated and compared by the Kaplan–Meier product-limit method and the log-rank test, respectively. Variables potentially affecting progression-free survival (PFS) were verified in univariate Cox proportional hazard models. The final multivariate Cox models were obtained with variables testing significant at the univariate analysis, and by adjusting for all plausible predictors of the outcome of interest (PFS). RESULTS: We observed a significant association between TAZ expression and Wnt mutations (Chi-squared p = 0.008). Combined TAZ expression and Wnt mutations (TAZ(pos)/WNT(mut)) was more frequently observed in patients with the shortest progression-free survival (negative outliers) (Fisher p = 0.021). Uni-and multivariate Cox regression analyses revealed that patients whose tumors harbored the TAZ(pos)/WNT(mut) signature had an increased risk of disease progression (univariate Cox: HR 2.27, 95% CI 1.27–4.05, p = 0.006; multivariate Cox: HR 2.73, 95% CI 1.41–5.29, p = 0.003). Finally, the TAZ(pos)/WNT(mut) signature negatively impacted overall survival. CONCLUSIONS: Collectively, our findings indicate that the oncogenic YAP/TAZ–Wnt crosstalk may be active in GC, conferring chemoresistant traits that translate into adverse survival outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1385-y) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-5800016
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-58000162018-02-13 Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy Melucci, Elisa Casini, Beatrice Ronchetti, Livia Pizzuti, Laura Sperati, Francesca Pallocca, Matteo De Nicola, Francesca Goeman, Frauke Gallo, Enzo Amoreo, Carla Azzurra Sergi, Domenico Terrenato, Irene Vici, Patrizia Di Lauro, Luigi Diodoro, Maria Grazia Pescarmona, Edoardo Barba, Maddalena Mazzotta, Marco Mottolese, Marcella Fanciulli, Maurizio Ciliberto, Gennaro De Maria, Ruggero Buglioni, Simonetta Maugeri-Saccà, Marcello J Transl Med Research BACKGROUND: An extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by oncogenic mutations. On this ground, we hypothesized that YAP/TAZ- and Wnt-related biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. METHODS: In the present study, we included 86 patients with advanced GC treated with first-line chemotherapy in prospective phase II trials or in routine clinical practice. Tissue samples were immunostained to evaluate the expression of YAP/TAZ. Mutational status of key Wnt pathway genes (CTNNB1, APC and FBXW7) was assessed by targeted DNA next-generation sequencing (NGS). Survival curves were estimated and compared by the Kaplan–Meier product-limit method and the log-rank test, respectively. Variables potentially affecting progression-free survival (PFS) were verified in univariate Cox proportional hazard models. The final multivariate Cox models were obtained with variables testing significant at the univariate analysis, and by adjusting for all plausible predictors of the outcome of interest (PFS). RESULTS: We observed a significant association between TAZ expression and Wnt mutations (Chi-squared p = 0.008). Combined TAZ expression and Wnt mutations (TAZ(pos)/WNT(mut)) was more frequently observed in patients with the shortest progression-free survival (negative outliers) (Fisher p = 0.021). Uni-and multivariate Cox regression analyses revealed that patients whose tumors harbored the TAZ(pos)/WNT(mut) signature had an increased risk of disease progression (univariate Cox: HR 2.27, 95% CI 1.27–4.05, p = 0.006; multivariate Cox: HR 2.73, 95% CI 1.41–5.29, p = 0.003). Finally, the TAZ(pos)/WNT(mut) signature negatively impacted overall survival. CONCLUSIONS: Collectively, our findings indicate that the oncogenic YAP/TAZ–Wnt crosstalk may be active in GC, conferring chemoresistant traits that translate into adverse survival outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1385-y) contains supplementary material, which is available to authorized users. BioMed Central 2018-02-05 /pmc/articles/PMC5800016/ /pubmed/29402328 http://dx.doi.org/10.1186/s12967-018-1385-y 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 Research
Melucci, Elisa
Casini, Beatrice
Ronchetti, Livia
Pizzuti, Laura
Sperati, Francesca
Pallocca, Matteo
De Nicola, Francesca
Goeman, Frauke
Gallo, Enzo
Amoreo, Carla Azzurra
Sergi, Domenico
Terrenato, Irene
Vici, Patrizia
Di Lauro, Luigi
Diodoro, Maria Grazia
Pescarmona, Edoardo
Barba, Maddalena
Mazzotta, Marco
Mottolese, Marcella
Fanciulli, Maurizio
Ciliberto, Gennaro
De Maria, Ruggero
Buglioni, Simonetta
Maugeri-Saccà, Marcello
Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
title Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
title_full Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
title_fullStr Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
title_full_unstemmed Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
title_short Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
title_sort expression of the hippo transducer taz in association with wnt pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800016/
https://www.ncbi.nlm.nih.gov/pubmed/29402328
http://dx.doi.org/10.1186/s12967-018-1385-y
work_keys_str_mv AT meluccielisa expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT casinibeatrice expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT ronchettilivia expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT pizzutilaura expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT speratifrancesca expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT palloccamatteo expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT denicolafrancesca expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT goemanfrauke expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT galloenzo expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT amoreocarlaazzurra expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT sergidomenico expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT terrenatoirene expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT vicipatrizia expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT dilauroluigi expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT diodoromariagrazia expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT pescarmonaedoardo expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT barbamaddalena expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT mazzottamarco expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT mottolesemarcella expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT fanciullimaurizio expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT cilibertogennaro expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT demariaruggero expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT buglionisimonetta expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy
AT maugerisaccamarcello expressionofthehippotransducertazinassociationwithwntpathwaymutationsimpactssurvivaloutcomesinadvancedgastriccancerpatientstreatedwithfirstlinechemotherapy