4113 Background: Clinical heterogeneity in gastric cancer is likely due to biological differences among patients. Molecular subtypes and their associated biomarkers need to be established to improve treatment of this disease. We aimed to uncover subgroups of gastric cancer that have distinct biological characteristics associated with clinical outcome and to identify potential best treatments or therapeutic targets for each subgroup. Methods: We analyzed gene expression profiling data from gastric cancer cell lines and 267 patients with gastric cancer to uncover tumor subtypes and identify a gene expression signature associated with prognosis and response to adjuvant chemotherapy. The association of the signature with prognosis was validated in an independent cohort of 200 patients, and its association with response to adjuvant therapy was validated by cell culture experiments. Results: We identified an expression signature of 88 genes that specifically reflected activation of the oncogene YAP1. Compared with patients without this signature, patients with the YAP1 signature had significantly poorer prognosis. In multivariate analysis, the signature was the strongest indicator of overall survival among all demographic and clinical variables examined together (hazard ratio, 2.1; 95% confidence interval, 1.3-3.3;P = .002). Activation of YAP1 was significantly associated with resistance to adjuvant chemotherapy. We also demonstrated that the Notch pathway is a potential therapeutic target for overcoming chemoresistance mediated by YAP1. Conclusions: Activation of the oncogene YAP1 is significantly associated with poorer survival of patients with gastric cancer and induces chemoresistance to this disease. Therefore, YAP1 may be highly attractive therapeutic target for patients with gastric cancer resistant to standard chemotherapy.
Combining gene expression signature with clinical features for survival stratification of gastric cancer
