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

Cristina L. Ronchi, Guido Di Dalmazi, Simon Faillot, Silviu Sbiera, Guillaume Assié, Isabel Weigand, Davide Calebiro, Thomas Schwarzmayr, Silke Appenzeller, Beatrice Rubin, Jens Waldmann, Carla Scaroni, Detlef K. Bartsch, Franco Mantero, Massimo Mannelli, Darko Kastelan, Iacopo Chiodini, Jerome Bertherat, Martin Reincke, Tim M. StromMartin Fassnacht, Felix Beuschlein

Research output: Contribution to journalArticlepeer-review


Context: Adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/protein kinase A signaling pathway are common in cortisolproducing 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, 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.

Original languageEnglish
Pages (from-to)3526-3538
Number of pages13
JournalJournal of Clinical Endocrinology and Metabolism
Issue number9
Publication statusPublished - Sep 1 2016

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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