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Ronchi, Cristina L.; Di Dalmazi, Guido; Faillot, Simon; Sbiera, Silviu; Assié, Guillaume; Weigand, Isabel; Calebiro, Davide; Schwarzmayr, Thomas; Appenzeller, Silke; Rubin, Beatrice; Waldmann, Jens; Scaroni, Carla; Bartsch, Detlef K.; Mantero, Franco; Mannelli, Massimo; Kastelan, Darko; Chiodini, Iacopo; Bertherat, Jerome; Reincke, Martin; Strom, Tim M.; Fassnacht, Martin; Beuschlein, Felix (2016): Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation. In: Journal of Clinical Endocrinology & Metabolism, Vol. 101, No. 9: pp. 3526-3538
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Context: Adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/protein kinase A signaling pathway are common in cortisol-producing ACAs, whereas activating mutations in the gene encoding beta-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear. Objective: The aim of the study was to define the genetic landscape of sporadic unilateral ACAs. Design and Setting: Next-generation whole-exome sequencing was performed on fresh-frozen tumor samples and corresponding normal tissue samples. Patients: Ninety-nine patients with ACAs (74 cortisol-producing and 25 endocrine inactive) negative for p.Leu206Arg PRKACA mutation. Main Outcome Measures: Identification of known and/or new genetic alterations potentially involved in adrenocortical tumorigenesis and autonomous hormone secretion, genotype-phenotype correlation. Results: A total of 706 somatic protein-altering mutations were detected in 88 of 99 tumors (median, six per tumor). We identified several mutations in genes of the cAMP/protein kinase A pathway, including three novel mutations in PRKACA, associated with female sex and Cushing's syndrome. We also found genetic alterations in different genes involved in the Wnt/beta-catenin pathway, associated with larger tumors and endocrine inactivity, and notably, inmanygenes of the Ca2+-signaling pathway. Finally, by comparison of our genetic data with those available in the literature, we describe a comprehensive genetic landscape of unilateral ACAs. Conclusions: This study provides the largest sequencing effort on ACAs to date. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis.