LowARID1AExpression is Associated with Poor Prognosis in Hepatocellular Carcinoma

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 lowARID1Aexpression in HCC. By analyzing the gene expression data of liver fromArid1a-knockout mice, hepaticArid1a-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 lackingArid1aactivity and was applied to gene expression data from three independent cohorts of HCC patients to stratify patients according toARID1Aactivity. The molecular features associated with loss ofARID1Awere analyzed using The Cancer Genome Atlas (TCGA) multi-platform data, and Ingenuity Pathway Analysis (IPA) was done to uncover potential signaling pathways associated withARID1Aloss.ARID1Ainactivation 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 theARID1A-low subtype thanARID1A-high subtype. Ingenuity pathway analysis revealed that direct upstream transcription regulators of theARID1Asignature were genes associated with cell cycle, includingE2Fgroup,CCND1,andMYC,while tumor suppressors such asTP53, SMAD3,andCTNNB1were significantly inhibited.ARID1Aplays an important role in immune activity and regulating multiple genes involved in HCC development. Low-ARID1Asubtype was associated with poor clinical outcome and suggests the possibility ofARID1Aas a prognostic biomarker in HCC patients.