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.

Abstract

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 (TAZpos/WNTmut) 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 TAZpos/WNTmut 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 TAZpos/WNTmut 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.

• Authors: Elisa Melucci, Beatrice Casini, Livia Ronchetti, Laura Pizzuti, Francesca Sperati, Matteo Pallocca, Francesca De Nicola, Frauke Goeman, Enzo Gallo, Carla Azzurra Amoreo, Domenico Sergi, Irene Terrenato, Patrizia Vici, Luigi Di Lauro, Maria Grazia Diodoro, Edoardo Pescarmona, Maddalena Barba, Marco Mazzotta, Marcella Mottolese, Maurizio Fanciulli, Gennaro Ciliberto, Ruggero De Maria, Simonetta Buglioni, Marcello Maugeri-Saccà
• Journal: Journal of translational medicine (J Transl Med) Vol. 16 Issue 1 Pg. 22 (02 05 2018) ISSN: 1479-5876 [Electronic] England
• PMID: 29402328 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Intracellular Signaling Peptides and Proteins
• Trans-Activators
• Transcription Factors
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• WWTR1 protein, human
• Protein Serine-Threonine Kinases

Topics

• Aged
• Biomarkers, Tumor (metabolism)
• Female
• Hippo Signaling Pathway
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Multivariate Analysis
• Mutation (genetics)
• Neoplasm Staging
• Proportional Hazards Models
• Protein Serine-Threonine Kinases (metabolism)
• Stomach Neoplasms (genetics, pathology)
• Survival Analysis
• Trans-Activators
• Transcription Factors
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• Treatment Outcome
• Wnt Signaling Pathway (genetics)