The advent of new genetic techniques that allow for high-throughput sequencing in surgical tumour tissues and germline DNA has boosted progress in many fields of biomedical research. The technique has been proven to be particularly fruitful in the area of endocrine tumours with many new driver genes being identified over the last few years that are involved in cell growth but more importantly in hormonal autonomy. Examples account for aldosterone producing adrenal adenomas, insulin producing neuroendocrine tumours, growth hormone producing pituitary adenomas and pheochromocytomas. Also, the field of Cushings syndrome has been moved forward on several fronts by identifying new genetic and molecular mechanisms that ultimately result in the clinical phenotype of hypercortisolism.
Following a whole genome sequencing approach in patients with familial cases of bilateral macronodular adrenal hyperplasia the group of Jérôme Bertherat identified germline mutations in the ARMC5 gene together with second hits in adrenal nodules as the cause of the disorder. This finding has not only opened the possibility to explore new pathophysiological mechanisms in adrenal steroidogenesis and cellular growth but also has led to the clinical application of genetic testing for case finding and prospective clinical follow-up. Based on exome sequencing from tumour tissue an European consortium was able to pinpoint mutations in the catalytic subunit of PKA (PRKACA) as the underlying genetic event in around one third of cases of cortisol producing adrenal adenomas. In addition, genetic duplications of the same gene were identified in a subgroup of patients from the NIH with bilateral micronodular hyperplasia. Interestingly, in the adenoma patients, there was a clear genotype/phenotype correlation with the most severe disease course in mutation carriers.
In summary, the last two years have witnessed significant progress in the elucidation of molecular mechanisms driving the clinical phenotype of endogenous hypercortisolism with all its metabolic and cardiovascular sequelae. The future will show how these findings will translate into clinically tangible progress.