Adrenocortical carcinoma (ACC) is a rare and often fatal cancer, affecting ~1 person per million per year worldwide. Approximately 75% of patients with ACC eventually develop metastases and progress on the few available standard-of-care medical therapies, highlighting an incredible need for an improved understanding of the molecular biology of this disease. Although it has long been known that ACC is characterized by certain histological and genetic features (e.g., high mitotic activity, chromosomal instability, and overexpression of IGF2), only in the last two decades of genomics has the molecular landscape of ACC been more thoroughly characterized. In this review, we describe the findings of historical genetics and recent genomics studies on ACC and discuss how underlying concepts emerging from these studies contribute to the current model of critical pathways for adrenocortical carcinogenesis. Integrative synthesis across these studies reveals that ACC consists of three distinct molecular subtypes with divergent clinical outcomes and implicates differential regulation of Wnt signaling, cell cycle, DNA methylation, immune biology, and steroidogenesis in ACC biology. These cellular programs are pharmacologically targetable and may enable the development of therapeutic strategies to improve outcomes for patients facing this devastating disease.
Keywords: adrenal; adrenocortical carcinoma; genomics; targeted therapy.