26O Comprehensive genomic analysis of adrenocortical carcinoma reveals genetic profiles associated with patient survival

Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with a median survival of only three to four years. While advancements have been achieved in elucidating the molecular mechanisms that underlie the pathogenesis of ACC, the translation of this knowledge into the realm of clinical therapeutics, has been limited. Therefore, there is a critical need for further identification of genetic markers that are related to clinical outcome in ACC patients. Genetic and clinical data from a total of 162 patients with ACC were analyzed by combining an independent cohort consisting of tumors from Yale School of Medicine, Karolinska Institutet, and Düsseldorf University (YKD) with two public databases (TCGA and GEO). The study included data from whole exome sequencing (WES) for the YKD cohort, WES and RNA data for the TCGA cohort and RNA data for the GEO cohort. Differentially expressed genes were analyzed using gene set enrichment analysis (GSEA) and hypergeometric analysis, and protein-protein interactions (PPI) were analyzed using disease association protein-protein link evaluator (DAPPLE). We identified 3,903 significant differentially expressed genes when comparing ACC and adrenocortical adenoma, and the mRNA expression levels of 461 of those genes significantly impacted survival. Subsequent analysis revealed 56 of those genes to be mutated in patients with significantly worse survival. This subgroup of patients exhibited a preference for the right adrenal gland when compared to the general cohort. Furthermore, PPI analysis revealed previously unexplored interactions amongst several of the 56 genes with implications for tumorigenesis. By combining several large ACC cohorts we identified 56 genes that significantly influence survival. Notably, many of these genes have oncogenic interactions that have not been previously implicated in ACC. These findings may lay the foundation for improved prognostication and future targeted therapies.