Low ARID1A Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma

Abstract

AT-rich interactive domain 1A (ARID1A) is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), but its clinical significance is not clarified. We aimed to evaluate the clinical significance of low ARID1A expression in HCC. By analyzing the gene expression data of liver from Arid1a-knockout mice, hepatic Arid1a-specific gene expression signature was identified (p < 0.05 and 0.5-fold difference). From this signature, a prediction model was developed to identify tissues lacking Arid1a activity and was applied to gene expression data from three independent cohorts of HCC patients to stratify patients according to ARID1A activity. The molecular features associated with loss of ARID1A were analyzed using The Cancer Genome Atlas (TCGA) multi-platform data, and Ingenuity Pathway Analysis (IPA) was done to uncover potential signaling pathways associated with ARID1A loss. ARID1A inactivation was clinically associated with poor prognosis in all three independent cohorts and was consistently related to poor prognosis subtypes of previously reported gene signatures (highly proliferative, hepatic stem cell, silence of Hippo pathway, and high recurrence signatures). Immune activity, indicated by significantly lower IFNG6 and cytolytic activity scores and enrichment of regulatory T-cell composition, was lower in the ARID1A-low subtype than ARID1A-high subtype. Ingenuity pathway analysis revealed that direct upstream transcription regulators of the ARID1A signature were genes associated with cell cycle, including E2F group, CCND1, and MYC, while tumor suppressors such as TP53, SMAD3, and CTNNB1 were significantly inhibited. ARID1A plays an important role in immune activity and regulating multiple genes involved in HCC development. Low-ARID1A subtype was associated with poor clinical outcome and suggests the possibility of ARID1A as a prognostic biomarker in HCC patients.