The pathway regulating RhoA activity to predict the survival of gastric cancers.

49 Background: RhoA mutation has been intensively studied for its association with progression in gastric cancer (GC). Recently, mutations in a pathway regulating RhoA activity have been identified as a predictive biomarker in breast cancer. Herein, our aim is to investigate the role of such pathway in the progression of patients with GC receiving chemotherapies. Methods: Two non-overlapped TCGA cohorts (TCGA1, downloaded from GDC, N = 123 and TCGA2, from Cbioportal, N = 312) and a third ACRG cohort (Nature Medicine 2015, N = 295) were assessed for their mutation status of RhoA pathway; meanwhile, a cohort from Chinese GC (CGC, N = 57) was examined with whole exome sequencing (WES). A subset of “Regulation of RhoA activity” pathway (NCI Pathway Interaction), denoted as RhoA_S, was derived from analyzing the expression of RhoA and mutations in TCGA1 without referring to its survival data. Subsequently, RhoA_S was evaluated for its prediction of overall survival (OS) in the above four GC cohorts receiving chemotherapies. Results: GCs with wild-type of RhoA_S as well as gain-of-function of RhoA mutation where the function of RhoA remained active were compared against those with mutated RhoA_S. The frequencies for the mutant RhoA_S were 46.3%, 24.0%, 16.3% and 50.9% for TCGA1, TCGA2, ACRG and CGC, respectively; while the “active” RhoA_S were found more unlikely to respond to chemotherapies and significantly associated with poor clinical outcomes in all four cohorts. The hazard ratios and p-values were 0.513, 0.009 for TCGA1; 0.509, 0.02 for TCGA2; 0.6, 0.04 for ACRG and 0.229, 0.014 for CGC, respectively. Conclusions: Four independent GC cohorts (totally 787 patients) validated RhoA_S as a predictive biomarker for their survival. Not only have our results confirmed gain-of-function in RhoA mutant facilitates the progression of GC patients, but also indicated the regulators of RhoA activity are implicated in their overall survival. This study has provided us an option to extend potentially druggable targets in highly malignant cancers with poor prognosis like GC.