Genetics and epigenetics of adrenocortical tumors

• Published in: Molecular and cellular endocrinology 2014-04, Vol.386 (1-2), p.67-84
• Main Authors: Lerario, Antonio M., Moraitis, Andreas, Hammer, Gary D.
• Format: Article
• Language: English
• Subjects: Activation; Adenoma; Adrenal Cortex - pathology; Adrenal Cortex - physiopathology; Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - pathology; Adrenal Cortex Neoplasms - physiopathology; Adrenocortical; Animals; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma; Disease Models, Animal; Epigenesis, Genetic; Epigenetics; Genetics; Humans; Hyperplasia; Medical services; Pathways; Profiling; Prognosis; Proposals; Signal Transduction - genetics; Tumors
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2013.10.028

•Abnormal PKA activation is present in most of cortisol-producing tumors.•Abnormal membrane depolarization leading to increased cytosolic calcium levels is present in the majority of APAs.•Although ACCs are usually sporadic, they can be a manifestation of rare cancer syndromes.•Subgroups of ACCs divided according to genetic and epigenetic markers have different prognosis.•Molecular-targeted therapies are expected to improve clinical responses in advanced ACCs. 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.