The gene encodes the class IA PI3K regulatory subunit p85α, which is frequently altered in cancer. functions as a tumor suppressor by stabilizing and inhibiting the catalytic activity of p110, and it directly binds to and enhances the activity of the PTEN lipid phosphatase. Aberrations in the gene are associated with poor prognosis in cancer; available data underscore the significant role of mutations in mediating tumorigenesis by promoting the signaling of the PI3K/AKT/mTOR pathway. Moreover, copy number variations, driver mutations, and epigenetic alterations in contribute to tumorigenesis and progression through distinct mechanisms. This article reviews the cancer-promoting effects of gene aberrations across major cancer types and elucidates their underlying mechanisms. It also discusses the targeted therapies for related aberrations, aiming to provide a comprehensive understanding of the dynamic interplay of in cancer, thereby advancing precision medicine and the development of targeted interventions.