Cristina L Ronchi1, Guido Di Dalmazi1, Simon Faillot1, Silviu Sbiera1, Guillaume Assié1, Isabel Weigand1, Davide Calebiro1, Thomas Schwarzmayr1, Silke Appenzeller1, Beatrice Rubin1, Jens Waldmann1, Carla Scaroni1, Detlef K Bartsch1, Franco Mantero1, Massimo Mannelli1, Darko Kastelan1, Iacopo Chiodini1, Jerome Bertherat1, Martin Reincke1, Tim M Strom1, Martin Fassnacht1, Felix Beuschlein1. 1. Department of Internal Medicine I (C.L.R., I.W., M.F.), Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, 97080 Wuerzburg, Germany; Medizinische Klinik und Poliklinik IV (G.D.D., M.R., F.B.), Klinikum der Universitaet Muenchen, 80337 Munich, Germany; Comprehensive Cancer Center Mainfranken (S.S., S.A., M.F.), University of Wuerzburg, 97080 Wuerzburg, Germany; Institut Cochin, Inserm U1016 (S.F., G.A., J.B.), CNRS UMR8104, Descartes University, 75006 Paris, France; Department of Endocrinology (S.F., G.A., J.B.), Reference Center for Rare Adrenal Diseases, Hôpital Cochin, 75014 Paris, France; Institute of Pharmacology and Toxicology and Bio-Imaging Center/Rudolf Virchow Center (D.C.), University of Wuerzburg, 97080 Wuerzburg, Germany; Institute of Human Genetics (T.S., T.M.S.), Helmholtz Zentrum Munich, 85764 Neuherberg, Germany; Core Unit System Medicine University of Wuerzburg (S.A.), 97080 Wuerzburg, Germany; Endocrinology Unit (B.R., C.S., F.M.), University Hospital of Padua, 35122 Padua, Italy; Department of Visceral, Thoracic, and Vascular Surgery (J.W., D.K.B.), University Hospital Giessen and Marburg, 35043 Marburg, Germany; Endocrinology Unit (M.M.), Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50121 Florence, Italy; Department of Endocrinology (D.K.), University Hospital Centre Zagreb, 10000 Zagreb, Croatia; Unit of Endocrinology and Metabolic Diseases (I.C.), Fondazione IRCCS Cá Granda-Ospedale Maggiore Policlinico, 20122 Milan, Italy; Institute of Human Genetics (T.M.S.), Technische Universität Munich, 80333 Munich, Germany; and Central Laboratory (M.F.), Research Unit, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.
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 Ca(2+)-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.
CONTEXT: Adrenocortical adenomas (ACAs) are among the most frequent humanneoplasias. 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.Leu206ArgPRKACA 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 Ca(2+)-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.
Authors: Juilee Rege; Jessie Hoxie; Chia-Jen Liu; Morgan N Cash; James M Luther; Lan Gellert; Adina F Turcu; Tobias Else; Thomas J Giordano; Aaron M Udager; William E Rainey; Kazutaka Nanba Journal: J Clin Endocrinol Metab Date: 2022-01-18 Impact factor: 6.134
Authors: Mark Sherlock; Andrew Scarsbrook; Afroze Abbas; Sheila Fraser; Padiporn Limumpornpetch; Rosemary Dineen; Paul M Stewart Journal: Endocr Rev Date: 2020-12-01 Impact factor: 19.871