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 (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.

Keywords: APC; CTNNB1; FBXW7; Gastric cancer; Hippo pathway; TAZ; Wnt pathway; YAP.

Fig. 1

a Oncoprint showing the distribution of the investigated biomarkers (YAP, TAZ, CTNNB1, APC, FBXW7) together with the cases with at least one mutations in Wnt pathway components (integrated pathway analysis). b MutationMapper illustrating the entire set of detected mutations (and their nature) represented on the linear proteins

Fig. 2

Kaplan–Meier survival curves of progression-free survival comparing TAZ^pos/WNT^mut cases versus their negative counterparts (N = 86)

Fig. 3

Kaplan–Meier survival curves of overall survival comparing TAZ^pos/WNT^mut cases versus their negative counterparts (N = 86). a Refers to overall survival calculated from the first cycle of chemotherapy, whereas b illustrates overall survival calculated from diagnosis