DNA and RNA sequencing identified a novel oncogene VPS35 in liver hepatocellular carcinoma

Liver hepatocellular carcinoma (LIHC) is the second leading cause of cancer mortality worldwide. Although cancer driver genes identified so far have been considered to be saturated or nearly saturated, challenges remain in discovering novel genes underlying carcinogenesis due to significant tumor heterogeneity. Here, in a small cohort of hepatitis B virus (HBV)-associated LIHC, we investigated the transcriptional patterns of tumor-mutated alleles using both whole-exome and RNA sequencing data. A graph clustering of the transcribed tumor-mutated alleles characterized overlapped functional clusters, and thus prioritized potentially novel oncogenes. We validated the function of the potentially novel oncogenes in vitro and in vivo. We showed that a component of the retromer complex-the vacuolar protein sorting-associated protein 35 (VPS35)-promoted the proliferation of hepatoma cell through the PI3K/AKT signaling pathway. In VPS35-knockout hepatoma cells, a significantly reduced distribution of membrane fibroblast growth factor receptor 3 (FGFR3) demonstrated the effects of VPS35 on sorting and trafficking of transmembrane receptor. This study provides insight into the roles of the retromer complex on carcinogenesis and has important implications for the development of personalized therapeutic strategies for LIHC.