Multi-omics profiling highlights karyopherin subunit alpha 2 as a promising biomarker for prognosis and immunotherapy respond in pediatric and adult adrenocortical carcinoma.

PURPOSE: Adrenocortical carcinoma (ACC) afflicts both pediatric and adult populations and is characterized by dismal prognosis and elevated mortality. Given the inconsistent therapeutic benefits and significant side effects associated with the conventional chemotherapy agent, mitotane, and the nascent stage of immunotherapy and targeted treatments, there is an urgent need to identify novel prognostic biomarkers and therapeutic targets in ACC. METHODS: Utilizing multi-omic datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), we employed Weighted Gene Co-expression Network Analysis (WGCNA), Cox regression, Receiver Operating Characteristic (ROC) curves, and survival analyses to sift for potential prognostic biomarkers. We subsequently validated these findings through immunohistochemistry and cell assays, and delved into the biological role of KPNA2 in ACC through functional enrichment analysis, mutational landscape, and immune cell infiltration. RESULTS: A total of 77 progression-associated genes with aberrant chromosomal accessibility were discerned within the TCGA-ACC dataset. By integrating ROC and Cox regression from GEO datasets, KPNA2 emerged as an independent risk factor portending poor outcomes in ACC. ATAC-seq analysis revealed attenuated chromatin accessibility of KPNA2 in cases with unfavorable prognosis. Immunohistochemistry corroborated elevated KPNA2 expression, which was linked to enhanced proliferation and invasion. Elevated KPNA2 levels were found to activate oncogenic pathways while simultaneously suppressing immunological responses. Immune infiltration analysis further revealed a decrement in CD8+ T-cell infiltration in KPNA2-high cohorts. CONCLUSION: This study demonstrates the clinical and biological significance of KPNA2 in ACC and suggests that KPNA2 could serve as a promising biomarker for predicting prognosis and immunotherapeutic responses in pediatric and adult ACC patients.