1. Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation
- Author
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Cristina L Ronchi, Felix Beuschlein, Silviu Sbiera, Martin Fassnacht, Carla Scaroni, Massimo Mannelli, Guido Di Dalmazi, Iacopo Chiodini, Beatrice Rubin, Jens Waldmann, Franco Mantero, Martin Reincke, Detlef K. Bartsch, Davide Calebiro, Thomas Schwarzmayr, Tim M. Strom, Silke Appenzeller, Guillaume Assié, Darko Kastelan, Jérôme Bertherat, Simon Faillot, Isabel Weigand, Ronchi, Cristina L, DI DALMAZI, Guido, Faillot, Simon, Sbiera, Silviu, Assié, Guillaume, Weigand, Isabel, Calebiro, Davide, Schwarzmayr, Thoma, Appenzeller, Silke, Rubin, Beatrice, Waldmann, Jen, Scaroni, Carla, Bartsch, Detlef K., Mantero, Franco, Mannelli, Massimo, Kastelan, Darko, Chiodini, Iacopo, Bertherat, Jerome, Reincke, Martin, Strom, Tim M., Fassnacht, Martin, Beuschlein, Felix, and University of Zurich
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,1303 Biochemistry ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,10265 Clinic for Endocrinology and Diabetology ,610 Medicine & health ,Context (language use) ,1308 Clinical Biochemistry ,Biology ,2704 Biochemistry (medical) ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Exome ,Protein kinase A signaling ,Gene ,Aged ,Cyclic AMP-Dependent Protein Kinase Catalytic Subunits ,Mutation ,Biochemistry (medical) ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Adrenal Cortex Neoplasms ,1310 Endocrinology ,PRKACA ,2712 Endocrinology, Diabetes and Metabolism ,030104 developmental biology ,030220 oncology & carcinogenesis ,Adrenocortical Adenoma ,Female ,Signal transduction ,Carcinogenesis ,Follow-Up Studies ,Hormone - Abstract
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 β-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/β-catenin pathway, associated with larger tumors and endocrine inactivity, and notably, in many genes 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.
- Published
- 2016