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

SIMPLE SUMMARY: Adult adrenocortical carcinoma (ACC) is a rare and aggressive tumor in adults, usually associated with excessive steroid secretion. It is highly metastatic and has few therapeutic options and a poor prognosis. Here, we explore the hallmarks of ACC influenced by transcription factors and their target genes (regulons) to provide a prognostic overview of ACC biology. Using an in silico clinical data analysis approach, we assessed human transcriptomic data from publicly available datasets. We found four distinct clusters of regulons associated with good and worse prognoses associated with cell proliferation and/or immunologic activity. Some findings require further bench analyses, primarily focusing on worse prognostic regulons and their targets. ABSTRACT: 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, NR5A1 (steroidogenic factor 1, SF-1) and CENPA (Centromeric Protein A), that were consistently associated with overall survival for further downstream analyses. The CENPA regulon was the primary regulator of MKI-67 (a marker of proliferation KI-67), while the NR5A1 regulon is a well-described transcription factor (TF) in ACC tumorigenesis. We also found that the ZBTB4 (Zinc finger and BTB domain-containing protein 4) regulon, which is negatively associated with CENPA 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.