ECE2016 Oral Communications Adrenal - Basic & Clinical (5 abstracts)
Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation
Cristina Ronchi 1 , Guido Di Dalmazi 2 , Silviu Sbiera 1 , Guillaume Assie 3 , Isabel Weigand 1 , Davide Calebiro 5 , Silke Appenzeller 6, , Beatrice Rubin 8 , Jens Waldmann 9 , Carla Scaroni 8 , Detlef Bartsch 9 , Franco Mantero 8 , Massimo Mannelli 10 , darko Kastelan 11 , Iacopo Chiodini 12 , Jerome Bertherat 3 , Martin Reincke 2 , Tim Strom 4 , Martin Fassnacht 1, & Felix Beuschlein 2
1Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital of Wuerzburg, Wuerzburg, Germany; 2Medizinische Klinik and Poliklinik IV, Ludwig-Maximilians-University Munich, Munich, Germany; 3Endocrinology, Cochin Institute, INSERM U1016, Paris, France; 4Institute of Human Genetics, Technical University of Munich, Munich, France; 5Institute of Pharmacology and Toxicology and Bio-Imaging Center/Rudolf Virchow Center, University of Wuerzburg, Wuerzburg, Germany; 6Core Unit Systems Medicine, University of Wuerzburg, Wuerzburg, Germany; 7Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany; 8Endocrinology Unit, University Hospital of Padua, Padua, Italy; 9Department of Visceral, Thoracic and Vascular Surgery, University Hospital Giessen and Marburg, Marburg, Germany; 10Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; 11Department of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia; 12Units of Endocrinology and Metabolic Diseases, Fondazione IRCCS Cá Granda-Ospedale Maggiore Policlinico, Milan, Italy.
Genetic alterations affecting the PKA/cAMP pathway are commonly found in cortisol-producing adrenocortical adenomas (ACAs), while activating mutations in the gene coding for β-catenin (CTNNB1) have been reported in both adenomas and carcinomas. However, the molecular pathogenesis of most ACAs is still unclear. Aim of the study was a comprehensive genetic characterization of sporadic ACAs and the identification of novel molecular markers involved in adrenal tumorigenesis and steroid autonomy.
Whole-exome sequencing was performed on DNA of adrenocortical tumors and corresponding blood samples of 99 patients with ACAs (39 associated with overt Cushing’s syndrome, 35 with subclinical hypercortisolism and 25 endocrine inactive) negative for the p.Leu206Arg PRKACA mutation.
In total, 706 protein-altering somatic mutations were detected in 88/99 ACAs (median: 6 mutations per sample, range: 0–55). Several altered genes could be recognized as part of the Wnt/β-catenin pathway (CTNNB1, APC, APC2, PKP2, and different members of the protocadherin superfamily), being associated with larger tumor size and endocrine inactivity. Moreover, many components of the cAMP/PKA pathway were affected by somatic mutations, including three new mutations in the PRKACA gene, mutations in metabotropic glutamate receptors (GRM3, GRM4, GRM6) and others (GNAS, PRKACA, PRKAR1A, CREB1, CREBBP, ADCY3), and associated with female gender and overt Cushing syndrome. Finally, more surprisingly, we also observed several alterations in genes involved in the Ca2+ signaling (CACNA1C, CACNA1E, RYR1, RYR2, RYR3, GRIA1, GRID1, GRIK2, GRIN1, GRIN3B, GRIP1, GRIA2).
In conclusion, this study represents the most comprehensive genetic characterization of unilateral ACAs, including inactive adenomas. We thereby identified somatic alterations affecting signaling pathways known or potentially involved in the adrenal tumorigenesis.
Volume 41
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Endocrine Abstracts
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