Biallelic ARID1A Alterations

Somatic mutations and copy number alterations of the adenine-thymine (AT)-rich interactive domain-containing protein 1A (ARID1A), a tumor suppressor gene, are associated with poor prognosis in many cancers, including adult hepatocellular carcinomas (HCC). In this study, ARID1A protein expression, clinicopathologic features, and outcomes were investigated in 59 pediatric malignant hepatocellular tumors (2004 to 2022) relative to ARID1A mutation and copy number status. Additional studies were performed on the impact of the loss of ARID1A protein expression on genomic instability, immune-cell infiltration, and PD-L1 protein expression. Twenty-three of the 59 (38.9%) children with malignant hepatocellular tumors (age: 0.4 to 13.8 y, M:F=2:1) harbored ARID1A alterations (mutations and/or copy number alterations). Nine tumors (15.2%) with biallelic alterations (ARID1A -/-) showed higher metastasis at presentation (P=0.01), were frequently CHIC high-risk (P=0.05), had aggressive histology (HCN-NOS and HCC) (P=0.002), and were negative for ARID1A immunohistochemistry (IHC) (100%). ARID1A loss by IHC was 100% sensitive and 98% specific, with 90% positive and 100% negative predictive value for ARID1A -/- tumors. ARID1A-negative tumors showed higher chromosomal instability (P=0.04), immune infiltrates (P=0.005), and PD-L1 expression by IHC (P=0.05). Patients with both ARID1A-negative and ARID1A-negative/PD-L1-positive tumors showed the lowest disease-specific survival in the intermediate and high CHIC-risk and all PRETEXT subgroups (P=ns). The association of biallelic ARID1A alterations with high-risk features and poor outcomes identifies ARID1A as a potential new biomarker in the risk stratification of children with malignant hepatocellular tumors. ARID1A IHC is a reliable tool to identify these aggressive tumors. Associated PD-L1 expression may offer new therapeutic options via checkpoint inhibitors.