Genetics and epigenetics of adrenocortical tumors

Adrenocortical tumors are common neoplasms. Most are benign, nonfunctional and clinically irrelevant. However, adrenocortical carcinoma is a rare disease with a dismal prognosis and no effective treatment apart from surgical resection. The molecular genetics of adrenocortical tumors remain poorly understood. For decades, molecular studies relied on a small number of samples and were directed to candidate-genes. This approach, based on the elucidation of the genetics of rare genetic syndromes in which adrenocortical tumors are a manifestation, has led to the discovery of major dysfunctional molecular pathways in adrenocortical tumors, such as the IGF pathway, the Wnt pathway and TP53. However, with the advent of high-throughput methodologies and the organization of international consortiums to obtain a larger number of samples and high-quality clinical data, this paradigm is rapidly changing. In the last decade, genome-wide expression profile studies, microRNA profiling and methylation profiling allowed the identification of subgroups of tumors with distinct genetic markers, molecular pathways activation patterns and clinical behavior. As a consequence, molecular classification of tumors has proven to be superior to traditional histological and clinical methods in prognosis prediction. In addition, this knowledge has also allowed the proposal of molecular-targeted approaches to provide better treatment options for advanced disease. This review aims to summarize the most relevant data on the rapidly evolving field of genetics of adrenal disorders.