YAP Activation Is Associated with a Worse Prognosis of Poorly Cohesive Gastric Cancer

Abstract

Poorly cohesive (PC) gastric cancer (GC) is extremely aggressive in progression, and there is an urgent need to identify the molecular pathways involved. We hypothesized the essential role of the RhoA-YAP axis in these mechanisms. The present observational multicenter retrospective study included 133 patients with PC GC treated at two dedicated European surgical centers between 2004 and 2014. YAP nuclear localization was measured by immunohistochemical (IHC) analysis of tissue biopsies. The complete absence of nuclear reactivity was coded as negative expression; we considered "any positive" as low nuclear expression (>0% but <10% of cells) and high nuclear expression (≥10% of cells). Women represented about half of the present series (52%), and the median age was 64 years (p25-p75 range: 53-75). Neoadjuvant and adjuvant treatments were administered to 10% and 54% of the cases, respectively. Extended systemic lymphadenectomy (D2) was the most common (54%). In nearly all cases, the number of retrieved nodes was ≥15, i.e., adequate for tumor staging (94%). An R0 resection was achieved in 80% of the cases. Most patients were pathological T stage 3 and 4 (pT3/pT4 = 79.0%) and pathological N stage 2, 3a, and 3b (pN2/pN3a/pN3b = 47.0%) at the pathological examination. Twenty patients (15%) presented distant metastases. Five-year overall survival (OS) was significantly higher (p = 0.029) in patients with negative YAP (46%, 95% CI 31.1-60.0%) than in the other patients (27%, 17.5-38.1%). Moreover, when controlling for sex, age, pT, pN, and percentage of signet ring cells in the multivariable analysis, YAP expression was a significant predictor of OS (HR 2.03, 95% CI: 1.18-3.51, p = 0.011). Our results provide new insights into the role of the YAP signaling cascade, as its activation was associated with a worse prognosis in PC GC.

Keywords: YAP expression; gastric cancer; poorly cohesive; tumor progression.

Figure 1

YAP-positive case 1. (A) Small-magnification section (6 mm) of YAP AT-stained gastric wall with submucosal infiltrating poorly cohesive cell carcinoma infiltrating the submucosa. (B) Detail at higher magnification (2 mm) of neoplastic cells in figure A, with nuclear and cytoplasmic expression of YAP AT involving the submucosa. (C) Higher magnification detail (300 µm) of figure B: positive neoplastic cells at the neoplastic advancement front.

Figure 2

YAP-positive case 2. (A) Hematoxylin&Eosin stained section at small magnification (5 mm) of ulcerated gastric wall with poorly cohesive cell carcinoma infiltrating the muscular tonaca propria and adipose tissue. (B) Higher magnification detail of A (2 mm): neoplastic cells, with nuclear and cytoplasmic expression of YAP AT involving the muscular tonaca propria. (C) Higher magnification detail (300 µm) of B: neoplastic cells, with nuclear and cytoplasmic expression of YAP AT involving the muscle tonaca propria.

Figure 3

(A): The overall survival curves, estimated using the Kaplan–Meier method, are a function of the YAP status: negative vs. positive. One YAP-positive subject was lost at follow-up. (B): Disease-related survival, estimated using the Kaplan–Meier method, is a function of YAP status: negative vs. positive. One YAP-positive subject was lost at follow-up.