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Jcem1109.Pdf JCEM ONLINE Advances in Genetics—Endocrine Research Identification of Gene Expression Profiles Associated With Cortisol Secretion in Adrenocortical Adenomas Hortense Wilmot Roussel,* Delphine Vezzosi,* Marthe Rizk-Rabin, Olivia Barreau, Bruno Ragazzon, Fernande René-Corail, Aurélien de Reynies, Jérôme Bertherat, and Guillaume Assie´ Institut National de la Santé et de la Recherche Médicale Unité 1016 (H.W.R., D.V., M.R.-R., O.B., B.R., Downloaded from https://academic.oup.com/jcem/article/98/6/E1109/2536811 by guest on 28 September 2021 F.R.-C., J.B., G.A.); Institut Cochin, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104 (H.W.R., D.V., M.R.-R, O.B., B.R., F.R.-C., J.B., G.A.); and Department of Endocrinology (H.W.R., O.B., J.B., G.A.), Reference Center for Rare Adrenal Diseases (J.B.), Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France; Faculté de Médecine Paris Descartes (H.W.R., D.V., M.R.-R., O.B., B.R., F.R.-C., J.B., G.A.), Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Department of Endocrinology (D.V.), Hôpital Larrey, 31480 Toulouse, France; and Plateforme de Bioinformatique (A.d.R.), Carte d’Identité des Tumeurs, Ligue Contre le Cancer, 75013 Paris, France Context: The cortisol secretion of adrenocortical adenomas can be either subtle or overt. The mechanisms leading to the autonomous hypersecretion of cortisol are unknown. Objective: The objective of the study was to identify the gene expression profile associated with the autonomous and excessive cortisol secretion of adrenocortical adenomas. Patients and Methods: The transcriptome of 22 unilateral adrenocortical adenomas (5 nonsecret- ing, 6 subclinical cortisol producing, 11 cortisol producing) was studied and correlated with cortisol secretion. Phosphodiesterase 8B (PDE8B) expression was measured by Western blot. Results: Unsupervised clustering identified 2 groups of adenomas with a difference in secretion level (P ϭ .008). Cluster 1 included only cortisol-producing adenomas (8 of 11), whereas cluster 2 was an admixture of the nonsecreting, the subclinical cortisol-secreting, and 3 of the 11 cortisol- secreting adenomas (Fisher exact, P ϭ .002). This cluster was driven by genes related to cortisol secretion and to extracellular matrix. More than 3000 genes correlated with cortisol secretion. Among the positively correlated were the steroidogenic enzymes, genes involved in cholesterol metabolism, and glutathione S-transferases. Among the negatively correlated genes were genes related to tran- scripts translation and the transcription factor GATA-6. The PDE8B, which inactivates the protein kinase A pathway, unexpectedly showed the strongest positive correlation with cortisol secretion, confirmed by Western blot. The protein kinase A-activity to cAMP ratio was increased in adenomas with high PDE8B levels, suggesting counterregulation to limit downstream activation of the pathway. Conclusion: The transcriptome of adrenocortical adenomas reveals a major association with cor- tisol secretion and identifies specific groups of genes implicated in steroid secretion, suggesting that cAMP signaling alterations might be frequent in cortisol-secreting adenomas. (J Clin Endo- crinol Metab 98: E1109–E1121, 2013) teroid hormones serve many essential roles in mam- regulated by the peptide hormone ACTH, which, upon S malian physiology, ranging from promoting devel- binding to the melanocortin 2 receptor, activates a cAMP/ opment to the regulation of metabolism. Under physio- protein kinase A (PKA)-dependent pathway. ACTH stim- logical conditions, cortisol biosynthesis is primarily ulation of the adrenal cortex is required for cortisol se- ISSN Print 0021-972X ISSN Online 1945-7197 * D.V. and H.W.R. contributed equally to this study. Printed in U.S.A. Abbreviations: COUP-TF, chicken ovalbumin upstream promoter-transcription factor; PDE, Copyright © 2013 by The Endocrine Society phosphodiesterase; PKA, protein kinase A. Received December 17, 2012. Accepted March 25, 2013. First Published Online March 28, 2013 doi: 10.1210/jc.2012-4237 J Clin Endocrinol Metab, June 2013, 98(6):E1109–E1121 jcem.endojournals.org E1109 E1110 Wilmot Roussel et al Transcriptome of Cortisol-Secreting Adenomas J Clin Endocrinol Metab, June 2013, 98(6):E1109–E1121 cretion because ACTH deficiency leads to adrenal cortex Patients and Methods atrophy and cortisol deficiency. Patients The second messenger, cAMP, is shown to be one of the Forty patients with operated unilateral adrenocortical benign most important regulatory signals for the control of cor- tumors were included. Surgery was indicated either for potential tisol steroidogenesis. Indeed, in vitro, ACTH can stimulate malignancy and/or cortisol secretion. Twenty-two tumors were a continuous increase in cAMP levels in the culture me- used for the transcriptome, and 25 tumors (including 7 also in- cluded in the transcriptome series) were studied by Western blot. dium, and cAMP analogs can induce the enzymes to the The tumor samples were prospectively collected in the cor- same levels as ACTH stimulation (1). Moreover, altera- tico-médullosurrénale, Tumeurs Endocrines (COMETE) net- tions of various components of the cAMP pathway from work tumor bank (6). Informed signed consent for the analysis of the tumors and access to the data collected was obtained from the cell surface to the nucleus have been observed in ad- Downloaded from https://academic.oup.com/jcem/article/98/6/E1109/2536811 by guest on 28 September 2021 all the patients, and the study was approved by the Institutional renal Cushing’s syndrome: somatic activating Gs muta- Review Board of the Cochin Hospital. tions in McCune-Albright syndrome, illegitimate expres- sion of the membrane receptors in ACTH-independent Hormonal exploration macronodular adrenal hyperplasia, inactivating muta- A detailed clinical and hormonal exploration was performed tions of the regulatory subunit R1A of PKA, and inacti- preoperatively, including 1 or 2 (median 1.5) 24-hour free uri- nary cortisol collections from each patient (CORT-CT2 compe- vating mutations of the phosphodiesterases 8B and 11A tition RIA kits; CIS Bio International, Gif sur Yvette, France), a (for review see Reference 2). midnight plasma cortisol measurement (Immulite 2000 Cortisol; Adrenocortical adenomas are benign tumors that can Diagnostics Products Corp, Los Angeles, California), and an cause ACTH-independent hypercortisolism. The molecu- early morning ACTH measurement (ELSA-ACTH; CIS Bio In- ternational). A dexamethasone suppression test was performed lar mechanisms responsible for cortisol overproduction preoperatively following different procedures: 1 mg at midnight despite the fact that low circulating ACTH levels are not suppression test (n ϭ 7), standard 2 mg/d suppression test (n ϭ well understood. Recently major advances have been 9), 8 mg at midnight suppression test (n ϭ 5). A short Synacthen made in understanding aldosterone-producing adenomas test was performed postoperatively in 21 patients. Cortisol-producing adenomas were defined by typical clinical with the identification of the potassium channel KCNJ5 signs and symptoms of Cushing’s syndrome and elevated free mutations, activating calcium signaling (3). To date, no urinary cortisol excretion (Ͼ90 ␮g/d). Subclinical cortisol-pro- single gene accounts for as many cortisol-producing tu- ducing adenomas were defined by the absence of clinically overt Cushing’s syndrome, normal 24-hour free urinary cortisol (Ͻ90 mors as KCNJ5 does for aldosterone-producing adeno- ␮g/d), and at least 1 biological alteration among the following: mas (up to approximately 20%). The expression profiles incomplete dexamethasone suppression [morning plasma corti- of several steroid-metabolizing enzymes and transcription sol of 28, 32, and 49 ng/mL after 1 mg of dexamethasone at factors from normal adjacent adrenals and cortisol-pro- midnight (n ϭ 3) or 24-hour free urinary cortisol between 11 and 21 mg/d during day 2 of the standard 2 mg/d dexamethasone ducing adenomas were compared (4, 5). It was shown that suppression (n ϭ 2)], low 8-hour plasma ACTH (Ͻ10 pg/mL), or the elevated production of cortisol in cortisol-producing disruption of the plasma cortisol circadian rhythm (0 hour to 8 adenomas is associated with an increased expression of hour serum cortisol ratio Ͼ 0.5). Nonsecreting adenomas were enzymes needed for corticosteroid production along with defined by the absence of clinical Cushing’s syndrome and a normal response to the tests described previously. For 1 nonse- alterations in transcription factors that enhance the ex- creting adenoma, the suppression test, the midnight cortisol, and pression of cortisol-metabolizing enzymes. However, a the 24-hour free urinary cortisol were missing, but the patient majority of these works do not provide a detailed corre- had a normal morning ACTH preoperatively and presented no lation between secretion level and gene expression. In- adrenal insufficiency a few days after surgery in addition to the absence of any clinical sign of hypercortisolism. For 1 subclinical deed, the tumors are usually classified as secreting or non- cortisol-producing adenoma, the 24-hour free urinary cortisol secreting, irrespective of the differences in secretion level. was missing, but the morning ACTH was not low (12 pg/mL), The condition of subclinical Cushing syndrome has been and the morning plasma cortisol was partially suppressed (49 especially poorly explored. ng/mL) after 1 mg of dexamethasone
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