CKS2, ERG28, ERP44, and FAM32A as Therapeutic-Responsive Oncogenic Biomarkers in Adrenocortical Carcinoma: A Multi-Omics, Systems-Level Analysis

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited therapies. To elucidate its post-transcriptional regulation, ceRNA networks were reconstructed from TCGA-ACC and GTEx 2025 data. Tumor networks exhibited compact topology and tumor-specific hub miRNAs (miR-466, miR-940, miR-507), which were downregulated, inversely correlated with oncogenic transcripts, and associated with adverse survival. Candidate targets were identified through dual validation by miRTarBase and miRDB, further confirmed with TargetScan, and filtered for inverse correlation, significant upregulation in tumors, and treatment-response association. The intersection of these stringent layers yielded four robust oncogenic biomarkers; CKS2, ERP44, ERG28, and FAM32A that were consistently upregulated and annotated to key processes: chromatin remodeling and cell cycle control (CKS2), apoptosis regulation (FAM32A), ER proteostasis and redox balance (ERP44), and sterol biosynthesis (ERG28). Network analysis highlighted CKS2 as central PPI hubs. Prognostic modeling demonstrated strong survival divergence, with CKS2 conferring the highest risk (HR = 4.49, p = 1.1e-06), while integration of the four-gene panel achieved near-perfect classification accuracy (AUC = 0.99). Collectively, these findings define CKS2, ERP44, ERG28, and FAM32A as high-confidence biomarkers in ACC, derived through multi-layered overlap filtering, and underscore their diagnostic and prognostic relevance.