Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis.

GPS is superior to NLR with respect to its prognostic value for patients with GBC after surgery with curative intent. GPS is not only associated with tumor progression but is also an independent marker of poor prognosis.

Abstract. Thioridazine, an antipsychotic drug, has been reported to induce apoptosis in various types of cancer cells, with specificity on targeting cancer stem cells (CSCs). However, whether it elicits anticancer effects in gastric cancer has never been reported. In the present study, we examined the ability of thioridazine to induce cell death in the gastric cancer cell lines NCI-N87 and AGS, and detected its in vivo tumor inhibition capacity. Thioridazine elicited cytotoxic effects on NCI-N87 and AGS cells in a dose-dependent manner, and inhibited the colony formation abilitiy of the NCI-N87 and AGS cells. Thioridazine treatment induced nuclear fragmentation, increased the proportion of sub-G1 phase cells, and elevated the percentage of Annexin V-positive cells, suggesting the occurrence of apoptosis. Moreover, thioridazine induced gastric cancer cell apoptosis in a caspase-dependent manner, as shown by a decrease in the precursors of casapse-9, caspase-8 and caspase-3, and by the ability of the caspase inhibitor Z-VAD-FMK to reverse the cytotoxic effect of thioridazine. JC-1 staining further revealed that thioridazine induced gastric cancer cell apoptosis via the mitochondrial pathway. In addition, thioridazine pretreatment inhibited the growth of NCI-N87 cell-derived tumors. The present study demonstrated that the antipsychotic drug thioridazine possesses anti-gastric cancer ability through in vitro and in vivo experiments, suggesting thioridazine as a potential drug in gastric cancer therapy. IntroductionGastric cancer is the fourth most common cancer worldwide with 989,600 new cases diagnosed in 2008, and it is the second leading cause of cancer-related death (1,2). Gastric cancer is either asymptomatic or causes non-specific symptoms at an early stage, and thus the majority of patients present with advanced stage disease at the time of initial diagnosis, leading to the poor prognosis of gastric cancer. Gastric cancer treatment involves surgery, chemotherapy, radiation therapy and their combinations. However, current drugs are confronted with low efficacy due to the high rate of patients at the advanced stage of gastric cancer. Thus, the development of novel effective drugs for gastric cancer therapy is urgently needed.Thioridazine, an antagonist of the dopamine receptor D2 family proteins, was initially developed as an antipsychotic drug, and recently its anticancer function was revealed. Studies have revealed the antiproliferative and apoptosis induction capacities of thioridazine in neuroblastoma, glioma, leukemia, breast cancer, cervical cancer and endometrial cancer (3-6). A gene signature-based approach identified thioridazine as an inhibitor of PI3K/Akt signaling in ovarian cancer cells. It downregulated cell cycle regulators cyclin D1 and CDK4, and upregulated p21, p16 and p-CDC25A, leading to the G0/ G1 phase arrest of the cells (7). Research on cervical and endometrial cancer cells disclosing the involvement of the PI3K/Akt/mTOR pathway in thioridazine-induced apoptosis further supported this fi...