MEK/ERK pathway characterization and its prognostic implication in gastric cancer (GC).

Abstract

e14552 Background: MEK/ERK pathway is considered one of the main controllers of cell proliferation and survival and its deregulation has been involved in several tumors. Different mechanisms have been described leading to ERK activation and nuclear translocation including mutations on genes encoding pathway constituents', or upstream factors overexpression. Little is known about the status of this pathway in GC. The aim of our study was to evaluate the expression of different factors of this pathway in GC and their correlation with patient outcome. Methods: Fifty-eight patients with localized stage Ib-III GC who underwent radical surgery followed by adjuvant chemoradiotherapy were selected. ERK and its activated form (pERK) expression were analyzed by IHC, and KRAS and BRAF mutations were determined by PCR. Additionally, expression of upstream factors such as EGFR, HER2, VEGFR and downstream factor such as MST2 was evaluated by IHC. Finally, EGFR and HER2 copy number alterations were analyzed by FISH. Association of these markers to overall survival was assessed using the log rank test, and survival curves were plotted with Kaplan-Meier methodology. Results: Among the 58 tumors analyzed, 7% arose from the cardias and 33% corresponded to signet ring cell carcinomas. ERK and pERK expression was observed in the majority of tumors (86 and 64%, respectively, p=0.002). Cytoplasmic pERK expression did not show any association with the clinico-pathological characteristics. Notably, nuclear pERK (pERKnc) expression was observed in 12% of the cases and it showed a significant correlation with patient survival (p=0.05), conferring a worse prognosis. Moreover, EGFR overexpression (p=0.03) correlated with pERKnc. Finally, multivariate Cox analysis for survival confirmed that stage (HR 0.31, p=0.01) and pERKnc (HR 2.7, p=0.04) are unique independent prognostic factors. Conclusions: MEK/ERK pathway is commonly activated in localized GC, backed up by ERK and pERK being highly expressed in these tumors. Moreover, EGFR expression correlates with nuclear ERK expression, suggesting that ERK translocation to the nucleus could be mediated by this factor. More importantly, nuclear ERK has appeared as an independent marker of poor prognosis.