Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed.

Sporadic adrenocortical tumours are common, but their pathogenesis is poorly elucidated. In this study, we present a meta-analysis and review of gene expression microarray and comparative genome hybridization (CGH) studies performed to date on these tumours, including our own data. Data of whole genome microarray studies from altogether 164 tumours (97 benign, 67 malignant) and 18 normal tissues were reclassified and reanalysed. Significant gene sets and cytogenetic changes from publications without available genomic data were also examined including 269 benign, 215 malignant tumour and 30 normal tissues. In our experimental study, 11 tumour and four normal samples were analysed by parallel mRNA and CGH profiling. Data were examined by an integrative bioinformatics approach (GeneSpring, Gene Set Enrichment Analysis and Ingenuity Pathway Analysis softwares) searching for common gene expression changes and paralleling chromosome aberrations. Both meta-analysis of available mRNA and CGH profiling data and our experimental study revealed three major pathogenetic pathways: (1) cell cycle, (2) retinoic acid signalling (including lipopolysaccharide/Toll like receptor 4 pathway), (3) complement system and antigen presentation. These pathways include novel, previously undescribed pathomechanisms of adrenocortical tumours, and associated gene products may serve as diagnostic markers of malignancy and therapeutic targets.

Steroid biosynthesis inhibitors in the therapy of hypercortisolism: theory and practice.

Cushing's syndrome is a rare disease with significant morbidity and mortality. Surgical intervention represents the most effective treatment option in both adrenocorticotropin-dependent and -independent forms of hypercortisolism. It is not uncommon, however, that surgery fails to cure or control the disease. Pharmacotherapy with drugs inhibiting steroid biosynthesis can be effectively used in these cases in order to alleviate symptoms or even to induce chemical adrenalectomy. A few drugs inhibiting single or multiple steps in adrenal steroid biosynthesis can be used in clinical practice. Drugs predominantly inhibiting single enzymatic steps include the 11beta-hydroxylase inhibitor metyrapone and the 3beta-hydroxysteroid dehydrogenase inhibitor trilostane, whereas mitotane, aminoglutethimide, ketoconazole and etomidate block multiple enzymatic reactions. Etomidate is the only agent available for parenteral administration that renders it as a treatment of choice in critically ill patients requiring a rapid control of hypercortisolemia. Ketoconazole, metyrapone and aminoglutethimide can be used alone or in combination for the treatment of hypercortisolism caused by benign adrenocorticotropin- or cortisol-secreting tumors. The clinical utility of trilostane is variable. Besides blocking multiple steps in adrenal steroid biosynthesis, the DDT (insecticide) analogue mitotane also has adrenolytic properties by inducing mitochondrial degeneration that renders it superior to other drugs in the treatment of adrenocortical cancer. Severe side effects may develop during therapy with each aforementioned drug that include hepatic, endocrine and neurological toxicity. After summarizing the chemical and biological properties of steroid biosynthetic inhibitors, the authors describe their possible clinical applications and limitations.