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

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 CilibertoMarcello Maugeri-Saccà

Research output: Contribution to journalComment/debate

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)247
JournalJournal of Translational Medicine
Volume16
Issue number1
DOIs
Publication statusPublished - Sep 4 2018

Fingerprint

Chemotherapy
Missense Mutation
Stomach Neoplasms
Mutation
Survival
Crosstalk
Transducers
Cells
Tissue
Drug Therapy
High-Throughput Nucleotide Sequencing
Wnt Signaling Pathway
Molecular Models
Disease-Free Survival
Disease Progression
Immunohistochemistry
Neoplasms
Therapeutics

Keywords

  • Gastric cancer
  • Hippo pathway
  • TP53 mutations
  • YAP

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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.

In: Journal of Translational Medicine, Vol. 16, No. 1, 04.09.2018, p. 247.

Research output: Contribution to journalComment/debate

Pallocca, M, Goeman, F, de Nicola, F, Melucci, E, Sperati, F, Terrenato, I, Pizzuti, L, Casini, B, Gallo, E, Amoreo, CA, Vici, P, di Lauro, L, Buglioni, S, Diodoro, MG, Pescarmona, E, Mazzotta, M, Barba, M, Fanciulli, M, de Maria, R, Ciliberto, G & Maugeri-Saccà, M 2018, '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, vol. 16, no. 1, pp. 247. https://doi.org/10.1186/s12967-018-1607-3
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. In: Journal of Translational Medicine. 2018 ; Vol. 16, No. 1. pp. 247.
@article{389704e9fa3e4521b4fa284e773ad445,
title = "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, 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.",
keywords = "Gastric cancer, Hippo pathway, TP53 mutations, YAP",
author = "Matteo Pallocca and Frauke Goeman and {de Nicola}, Francesca and Elisa Melucci and Francesca Sperati and Irene Terrenato and Laura Pizzuti and Beatrice Casini and Enzo Gallo and Amoreo, {Carla Azzurra} and Patrizia Vici and {di Lauro}, Luigi and Simonetta Buglioni and Diodoro, {Maria Grazia} and Edoardo Pescarmona and Marco Mazzotta and Maddalena Barba and Maurizio Fanciulli and {de Maria}, Ruggero and Gennaro Ciliberto and Marcello Maugeri-Sacc{\`a}",
year = "2018",
month = "9",
day = "4",
doi = "10.1186/s12967-018-1607-3",
language = "English",
volume = "16",
pages = "247",
journal = "Journal of Translational Medicine",
issn = "1479-5876",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer

AU - Pallocca, Matteo

AU - Goeman, Frauke

AU - de Nicola, Francesca

AU - Melucci, Elisa

AU - Sperati, Francesca

AU - Terrenato, Irene

AU - Pizzuti, Laura

AU - Casini, Beatrice

AU - Gallo, Enzo

AU - Amoreo, Carla Azzurra

AU - Vici, Patrizia

AU - di Lauro, Luigi

AU - Buglioni, Simonetta

AU - Diodoro, Maria Grazia

AU - Pescarmona, Edoardo

AU - Mazzotta, Marco

AU - Barba, Maddalena

AU - Fanciulli, Maurizio

AU - de Maria, Ruggero

AU - Ciliberto, Gennaro

AU - Maugeri-Saccà, Marcello

PY - 2018/9/4

Y1 - 2018/9/4

N2 - 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.

AB - 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.

KW - Gastric cancer

KW - Hippo pathway

KW - TP53 mutations

KW - YAP

UR - http://www.scopus.com/inward/record.url?scp=85052975089&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052975089&partnerID=8YFLogxK

U2 - 10.1186/s12967-018-1607-3

DO - 10.1186/s12967-018-1607-3

M3 - Comment/debate

AN - SCOPUS:85052975089

VL - 16

SP - 247

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

IS - 1

ER -