Comprehensive Characterization of the Regulatory Landscape of Adrenocortical Carcinoma: Novel Transcription Factors and Targets Associated with Prognosis.

We reconstructed a transcriptional regulatory network for adrenocortical carcinoma (ACC) using transcriptomic and clinical data from The Cancer Genome Atlas (TCGA)-ACC cohort. We investigated the association of transcriptional regulatory units (regulons) with overall survival, molecular phenotypes, and immune signatures. We annotated the ACC regulons with cancer hallmarks and assessed single sample regulon activities in the European Network for the Study of Adrenal Tumors (ENSAT) cohort. We found 369 regulons associated with overall survival and subdivided them into four clusters: RC1 and RC2, associated with good prognosis, and RC3 and RC4, associated with worse outcomes. The RC1 and RC3 regulons were highly correlated with the 'Steroid Phenotype,' while the RC2 and RC4 regulons were highly correlated with a molecular proliferation signature. We selected two regulons, (steroidogenic factor 1, SF-1) and (Centromeric Protein A), that were consistently associated with overall survival for further downstream analyses. The regulon was the primary regulator of (a marker of proliferation KI-67), while the regulon is a well-described transcription factor (TF) in ACC tumorigenesis. We also found that the (Zinc finger and BTB domain-containing protein 4) regulon, which is negatively associated with in our transcriptional regulatory network, is also a druggable anti-tumorigenic TF. We anticipate that the ACC regulons may be used as a reference for further investigations concerning the complex molecular interactions in ACC tumors.