Guido Di Dalmazi1, Caroline Kisker, Davide Calebiro, Massimo Mannelli, Letizia Canu, Giorgio Arnaldi, Marcus Quinkler, Nada Rayes, Antoine Tabarin, Marie Laure Jullié, Franco Mantero, Beatrice Rubin, Jens Waldmann, Detlef K Bartsch, Renato Pasquali, Martin Lohse, Bruno Allolio, Martin Fassnacht, Felix Beuschlein, Martin Reincke. 1. Medizinische Klinik und Poliklinik IV (G.D.D., M.F., F.B., M.R.), Klinikum der Universität München, München, Germany; Rudolf Virchow Center for Experimental Biomedicine (C.K., D.C., M.L.), University of Würzburg, Würzburg, Germany; Institute of Pharmacology and Toxicology (D.C., M.L.), University of Würzburg, 97080 Würzburg, Germany; Department of Experimental and Clinical Biomedical Sciences (M.M., L.C.), Florence, Italy; Endocrinology Division, Department of Clinical and Molecular Sciences (G.A.), University Hospital, Ancona, Italy; Bereich Klinische Endokrinologie, Charité Campus Mitte (M.Q.), Charité Universitätsmedizin, Berlin, Germany; Department of General, Visceral, and Transplant Surgery (N.R.), Charité Campus Virchow Clinic, Berlin, Germany; Department of Endocrinology (A.T.), Centre Hospitalier Universitaire Bordeaux and University of Bordeaux, Bordeaux, France; Service d'Anatomopathologie (L.J.), Centre Hospitalier Universitaire Bordeaux and University of Bordeaux, Bordeaux, France; Endocrinology Unit, Department of Medicine (F.M., B.R.), University of Padua, Padua, Italy; Klinik für Visceral, Thorax, und Gefäßchirurgie (J.W., D.K.B.), Marburg, Germany; Endocrinology Unit, Department of Medical and Surgical Sciences (R.P.), Alma Mater University of Bologna, Bologna, Italy; Endocrine and Diabetes Unit, Department of Internal Medicine I (B.A.), University Hospital, University of Würzburg, Würzburg, Germany; and Comprehensive Cancer Center Mainfranken (M.F.), University of Würzburg, Germany.
Abstract
CONTEXT: Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortical masses. METHODS: Samples from nine European centers were included (Germany, n = 4; Italy, n = 4; France, n = 1). Samples were drawn from 149 patients with nonsecreting adenomas (n = 32 + 2 peritumoral), subclinical hypercortisolism (n = 36), Cushing's syndrome (n = 64 + 2 peritumoral), androgen-producing tumors (n = 4), adrenocortical carcinomas (n = 5 + 2 peritumoral), and primary bilateral macronodular adrenal hyperplasias (n = 8). Blood samples were available from patients with nonsecreting adenomas (n = 15), subclinical hypercortisolism (n = 10), and Cushing's syndrome (n = 35). Clinical and hormonal data were collected. DNA amplification by PCR of exons 6 and 7 of the PRKACA gene and direct sequencing were performed. RESULTS: PRKACA heterozygous mutations were found in 22/64 samples of Cushing's syndrome patients (34%). No mutations were found in peritumoral tissue and blood samples or in other tumors examined. The c.617A>C (p.Leu206Arg) occurred in 18/22 patients. Furthermore, two novel mutations were identified: c.600_601insGTG/p.Cys200_Gly201insVal in three patients and c.639C>G+c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg) in one. All the mutations involved a region implicated in interaction between PKA regulatory and catalytic subunits. Patients with somatic PRKACA mutations showed higher levels of cortisol after dexamethasone test and a smaller adenoma size, compared with nonmutated subjects. CONCLUSIONS: These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome.
CONTEXT: Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortical masses. METHODS: Samples from nine European centers were included (Germany, n = 4; Italy, n = 4; France, n = 1). Samples were drawn from 149 patients with nonsecreting adenomas (n = 32 + 2 peritumoral), subclinical hypercortisolism (n = 36), Cushing's syndrome (n = 64 + 2 peritumoral), androgen-producing tumors (n = 4), adrenocortical carcinomas (n = 5 + 2 peritumoral), and primary bilateral macronodular adrenal hyperplasias (n = 8). Blood samples were available from patients with nonsecreting adenomas (n = 15), subclinical hypercortisolism (n = 10), and Cushing's syndrome (n = 35). Clinical and hormonal data were collected. DNA amplification by PCR of exons 6 and 7 of the PRKACA gene and direct sequencing were performed. RESULTS:PRKACA heterozygous mutations were found in 22/64 samples of Cushing's syndromepatients (34%). No mutations were found in peritumoral tissue and blood samples or in other tumors examined. The c.617A>C (p.Leu206Arg) occurred in 18/22 patients. Furthermore, two novel mutations were identified: c.600_601insGTG/p.Cys200_Gly201insVal in three patients and c.639C>G+c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg) in one. All the mutations involved a region implicated in interaction between PKA regulatory and catalytic subunits. Patients with somatic PRKACA mutations showed higher levels of cortisol after dexamethasone test and a smaller adenoma size, compared with nonmutated subjects. CONCLUSIONS: These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome.
Authors: Maya B Lodish; Bo Yuan; Isaac Levy; Glenn D Braunstein; Charalampos Lyssikatos; Paraskevi Salpea; Eva Szarek; Alexander S Karageorgiadis; Elena Belyavskaya; Margarita Raygada; Fabio Rueda Faucz; Louise Izzat; Caroline Brain; James Gardner; Martha Quezado; J Aidan Carney; James R Lupski; Constantine A Stratakis Journal: Eur J Endocrinol Date: 2015-06 Impact factor: 6.664
Authors: N M Albiger; D Regazzo; B Rubin; A M Ferrara; S Rizzati; E Taschin; F Ceccato; G Arnaldi; F Pecori Giraldi; A Stigliano; L Cerquetti; F Grimaldi; E De Menis; M Boscaro; M Iacobone; G Occhi; C Scaroni Journal: Endocrine Date: 2016-04-19 Impact factor: 3.633