The somatic mutational landscape and role of the ARID1A gene in hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Clarification of the somatic mutational landscape of important genes could reveal new therapeutic targets and facilitate individualized therapeutic approaches for HCC patients. The mutation and expression changes in the ARID1A gene in HCC remain controversial.Methods: First, cBioPortal was used to visualize genetic alterations and DNA copy number al-terations (CNAs) in ARID1A. The relationships between ARID1A mutation status and HCC patient clinicopathological features and overall survival (OS) were also determined. Then, a meta -analysis was performed to evaluate the effect of ARID1A mutation or expression on the prog-nosis of HCC patients. Finally, the role of ARID1A in HCC progression was verified by in vitro experiments.Results: ARID1A mutation was detected in 9.35% (33/353) of sequenced HCC cases, and ARID1A mutation decreased ARID1A mRNA expression. Patients with ARID1A alterations presented worse OS than those without ARID1A alterations. Meta-analysis and human HCC tissue microarray (TMA) analysis revealed that HCC patients with low ARID1A expression had worse OS and relapse-free survival (RFS), and low ARID1A expression was negatively correlated with tumour size. Then, ARID1A gain-of-function and loss-of-function experiments demonstrated the tumour suppressor role of ARID1A in HCC in vitro. In terms of the mechanism, we found that ARID1A could inhibit HCC progression by regulating retinoblastoma-like 1 (RBL1) expression via the JNK/ FOXO3 pathway.Conclusions: ARID1A can be considered a potential prognostic biomarker and candidate thera-peutic target for HCC.