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Ronchi, C.L.* ; di Dalmazi, G.* ; Faillot, S.* ; Sbiera, S.* ; Assié, G.* ; Weigand, I.* ; Calebiro, D.* ; Schwarzmayr, T. ; Appenzeller, S.* ; Rubin, B.K.* ; Waldmann, J.* ; Scaroni, C.* ; Bartsch, D.K.* ; Mantero, F.* ; Mannelli, M.* ; Kastelan, D.* ; Chiodini, I.* ; Bertherat, J.* ; Reincke, M.* ; Strom, T.M. ; Fassnacht, M.* ; Beuschlein, F.*

Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation.

J. Clin. Endocrinol. Metab. 101, 3526-3538 (2016)
Publ. Version/Full Text Supplement DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
CONTEXT: adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/PKA signaling pathway are common in cortisol-producing ACAs, while 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: 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: 99 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: 706 somatic protein-altering mutations were detected in 88/99 tumors (median: 6 per tumor). We identified several mutations in genes of the cAMP/PKA 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 up to now. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adrenal Cushings-syndrome; Pka Catalytic Subunit; Protein-kinase-a; Somatic Mutations; Genomic Characterization; Extracellular-matrix; Pituitary-adenomas; Beta-catenin; Tumors; Expression
ISSN (print) / ISBN 0021-972X
e-ISSN 1945-7197
Journal Journal of Clinical Endocrinology & Metabolism, The
Quellenangaben Volume: 101, Issue: 9, Pages: 3526-3538 Article Number: , Supplement: ,
Publisher Endocrine Society
Publishing Place Bethesda, Md.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)