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.

Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation / C.L. Ronchi, G. Di Dalmazi, S. Faillot, S. Sbiera, G. Assié, I. Weigand, D. Calebiro, T. Schwarzmayr, S. Appenzeller, B. Rubin, J. Waldmann, C. Scaroni, D.K. Bartsch, F. Mantero, M. Mannelli, D. Kastelan, I. Chiodini, J. Bertherat, M. Reincke, T.M. Strom, M. Fassnacht, F. Beuschlein. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 101:9(2016), pp. 3526-3538. [10.1210/jc.2016-1586]

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

C.L. Ronchi
;
D. Calebiro;I. Chiodini;
2016

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 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.
Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Adult; Aged; Biomarkers, Tumor; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; Exome; Female; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutation; Endocrinology, Diabetes and Metabolism; Biochemistry; Endocrinology; Clinical Biochemistry; Biochemistry (medical)
Settore MED/13 - Endocrinologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
96 - Genetic landscape of sporadic AI - JCEM 2016.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 1.17 MB
Formato Adobe PDF
1.17 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/616047
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 47
  • ???jsp.display-item.citation.isi??? 42
social impact