Molecular interplay of ARID1A in gastrointestinal cancers.

Abstract

ARID1A is a subunit of the SWI/SNF chromatin remodeling complex that plays a dual role in cancer biology as a tumor suppressor or an oncogene dependent on the cellular context. It is frequently found to be altered in gastrointestinal (GI) cancers esophageal, gastric, hepatocellular, pancreatic and colorectal carcinomas. With approximate mutation rates of 19-20% in gastric and colorectal cancers and up to 10% across all tumors. ARID1A regulates gene expression, genomic stability, and major oncogenic pathways like PI3K/AKT and YAP/TAZ. Its loss has been associated with poor prognosis, increased tumor aggressiveness and pronounced resistance to treatment. In gastric carcinoma, the lack of ARID1A correlates with enhanced tumor invasiveness, poor survival, and immune checkpoint expression offering therapeutic interventions with PARP inhibitors and advanced immunotherapies. Similarly in colorectal cancer, ARID1A alterations are related to microsatellite instability (MSI), affecting tumor behavior and immune responses. In contrast, hepatocellular carcinoma in the absence of ARID1A promotes angiogenesis and tumor progression, while pancreatic cancer displays its role in epithelial-mesenchymal transition (EMT) and metastasis by YAP/TAZ pathway activation. Moreover, miRNA-mediated regulation of ARID1A modulates tumor progression and provides resistance to treatment, for instance, miR-129-5p and miR-3613-3p have been implicated in prognosis. Alongside genetic and molecular studies, our bioinformatics analyses reveal considerable heterogeneity in ARID1A mutational signatures and expression across GI cancers, underscoring its stage-specific prognostic and therapeutic implications. The coexistence of truncating and missense variants further highlights the need for mechanistic validation, and integrative pathway analysis to identify synthetic lethal targets and improve the therapeutic strategies. Integrating ARID1A into precision oncology is a promising approach for improving the diagnostic, prognostic, and treatment modalities for patients with ARID1A-deficient cancers.