OR17-Novel Aspects of Adrenal Tumors and the HPA Axis

ENDO_2015

 

March 06, 2015

OR17-Novel Aspects of Adrenal Tumors and the HPA Axis

Epigenetic modulation of DNA Is associated with fatigue, depression and anxiety in patients with Cushing’s syndrome in remission: A genome-wide methylation study

CAM Glad, JC Andersson-Assarsson, P Berglund, R Bergthorsdottir, O Ragnarsson, G Johannsson

Summary: Researchers conducted this study to determine whether patients with Cushing’s syndrome (CS) that is in remission have specific epigenetic alterations that are associated with persistent cognitive impairments, anxiety, fatigue, and depression. Patients with CS in remission were shows to have specific DNA methylation that differed from that of healthy controls and was strongly correlated with clinical traits of anxiety, depression and fatigue, they concluded, adding that their results may suggest that an interaction between the glucocorticoid and the retinoic acid receptor is implicated in the long-term outcome of patients with CS in remission. The persistent cognitive impairment observed in patients with CS in remission, therefore, may be due to epigenetic modulation of DNA, they concluded.

Methods:

  • For this cross-sectional, case-controlled, single center study, researchers included 48 women with CS in remission (mean age±SD: 52.9±14 years) and 16 controls (mean age±SD: 53.6±16 years) matched for age, gender and educational level.
  • The mean age at diagnosis of CS was 37±14 years and the median (interquartile range) duration of remission was 13 (5-19) years.
  • In all, 37 patients had Cushing’s disease (CD) and 11 had a cortisol producing adrenal adenoma.
  • Researchers used the fatigue impact scale (FIS) to evaluate fatigue, and the comprehensive psychopathological rating scale to evaluate depression and anxiety; they assessed cognitive function by standardized neuropsychological tests.
  • DNA was isolated from whole blood, and DNA methylation was analyzed on the Illumina Infinium HumanMethylation450K BeadChip, which simultaneously interrogates >465,000 methylation sites per sample.
  • Researchers performed data quality control and analysis using the ChAMP methylation analysis package in R, and used Spearmen’s rho to perform correlation analyses.

Results:

  • Researchers found that patients had higher median score for FIS, depression and anxiety.
  • Methylation analysis identified 3,903 probes (in 340 genes) in regions that were differently methylated between CS patients and controls, and they found that 28% of these were significantly correlated to at least one of the clinical traits.
  • Fatigue, depression and anxiety were the most commonly correlated traits, and two of the most highly correlated genes were RXRB and COL11A2.
  • Gene ontology analysis revealed that these belong to the same GO-terms and are involved in retinoic acid receptor activity.
  • Finally, researchers found that both genes were specifically hypomethylated in cases as compared to controls.

 

This project has received financial support from the Swedish federal government under the LUA/ALF agreement, The Health & Medical Care Committee of the Regional Executive Board, Region VÀstra Götaland, The Swedish Society of Medicine and The Swedish Society of Endocrinology.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ5BA369FDE9DE4CED82CB6A7CD5BFD1BE/42321/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ENDO2015&nonus=0

ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing’s Syndrome

adrenal-hyperplasia

 

Guillaume Assié, M.D., Ph.D., Rossella Libé, M.D., Stéphanie Espiard, M.D., Marthe Rizk-Rabin, Ph.D., Anne Guimier, M.D., Windy Luscap, M.Sc., Olivia Barreau, M.D., Lucile LefÚvre, M.Sc., Mathilde Sibony, M.D., Laurence Guignat, M.D., Stéphanie Rodriguez, M.Sc., Karine Perlemoine, B.S., Fernande René-Corail, B.S., Franck Letourneur, Ph.D., Bilal Trabulsi, M.D., Alix Poussier, M.D., Nathalie Chabbert-Buffet, M.D., Ph.D., Françoise Borson-Chazot, M.D., Ph.D., Lionel Groussin, M.D., Ph.D., Xavier Bertagna, M.D., Constantine A. Stratakis, M.D., Ph.D., Bruno Ragazzon, Ph.D., and JérÎme Bertherat, M.D., Ph.D.

N Engl J Med 2013; 369:2105-2114 November 28, 2013 DOI: 10.1056/NEJMoa1304603

BACKGROUND

Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing’s syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.

METHODS

We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models.

RESULTS

The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.

CONCLUSIONS

Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.)

Supported in part by grants from Agence Nationale de la Recherche (ANR-10-Blan-1136), CorticomedullosurrĂ©nale Tumeur Endocrine Network (Programme Hospitalier de Recherche Clinique grant AOM95201), Assistance Publique–HĂŽpitaux de Paris (Clinical Research Center Grant Genhyper P061006), Institut National du Cancer (Recherche Translationelle 2009-RT-02), the Seventh Framework Program of the European Commission (F2-2010-259735), INSERM (Contrat d’Interface, to Dr. AssiĂ©), the Conny-Maeva Charitable Foundation, and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Assié, Libé, Espiard, Rizk-Rabin, Ragazzon, and Bertherat contributed equally to this article.

We thank Drs. J. Chelly and M. Delpech of the cell bank of Cochin Hospital and Dr. B. Terris of the tumor bank of Cochin Hospital for their help in sample collection; Dr. E. Clauser of the oncogenetic unit of Cochin Hospital for help in microsatellite analysis; Drs. J. Guibourdenche and E. Clauser of the hormone biology unit of Cochin Hospital for cortisol assays; Drs. F. Tissier and Pierre Colin for pathological analysis; Anne Audebourg for technical assistance; J. Metral and A. de Reynies of the Cartes d’IdentitĂ© des Tumeurs program of Ligue Nationale contre le Cancer for help in genomics studies and fruitful discussions; Dr. P. Nietschke of the bioinformatics platforms of Paris Descartes University for helpful discussions; all the members of the Genomics and Signaling of Endocrine Tumors team and of the genomic platform of Cochin Institute for their help in these studies; and the patients and their families, as well as the physicians and staff involved in patient care, for their active participation.

SOURCE INFORMATION

From INSERM UnitĂ© 1016, Centre National de la Recherche Scientifique UnitĂ© Mixte de Recherche 8104, Institut Cochin (G.A., R.L., S.E., M.R.-R., A.G., W.L., O.B., L.L., S.R., K.P., F.R.-C., F.L., L. Groussin, X.B., B.R., J.B.), FacultĂ© de MĂ©decine Paris Descartes, UniversitĂ© Paris Descartes, Sorbonne Paris CitĂ© (G.A., S.E., A.G., O.B., L.L., M.S., K.P., F.R.-C., L. Groussin, X.B., J.B.), Department of Endocrinology, Referral Center for Rare Adrenal Diseases (G.A., R.L., O.B., L. Guignat, L. Groussin, X.B., J.B.), and Department of Pathology (M.S.), Assistance Publique–HĂŽpitaux de Paris, HĂŽpital Cochin, and Unit of Endocrinology, Department of Obstetrics and Gynecology, HĂŽpital Tenon (N.C.-B.) — all in Paris; Unit of Endocrinology, Centre Hospitalier du Centre Bretagne, Site de KĂ©rio, Noyal-Pontivy (B.T.), Unit of Endocrinology, HĂŽtel Dieu du Creusot, Le Creusot (A.P.), and Department of Endocrinology Lyon-Est, Groupement Hospitalier Est, Bron (F.B.-C.) — all in France; and the Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics and the Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.).

Address reprint requests to Dr. Bertherat at Service des Maladies Endocriniennes et Métaboliques, Centre de Référence des Maladies Rares de la Surrénale, HÎpital Cochin, 27 rue du Faubourg St. Jacques, 75014 Paris, France, or at jerome.bertherat@cch.aphp.fr.

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Cushing’s Syndrome, Prostate Cancer and Adrenocortical Carcinoma

Orphagen has identified and characterized small molecule antagonists to steroidogenic factor-1 (SF-1). SF-1 binds to and regulates DNA promoter elements in the major transporters and enzymes required for adrenal steroid synthesis. It is also required for development of the adrenal gland. SF-1 antagonists inhibit cortisol secretion in adrenal cells and have potential application in two orphan indications, Cushing’s syndrome and adrenocortical carcinoma. In addition, SF-1 appears to have an important role in the progression of advanced prostate cancer.

 

cushings-adrenocortical-crop

 

Cushing’s syndrome:
An estimated 20,000 people in the US have Cushing’s, with more than 3,000 new cases diagnosed each year. The incidence is similar in Europe. Cushing’s syndrome disproportionately affects females, who make up about 75% of the diagnosed cases. Symptoms of Cushing’s syndrome can include obesity, diabetes, psychiatric disorders, osteoporosis and immune suppression. Cushing’s syndrome is caused by elevated secretion of cortisol from the adrenal gland, in association with pituitary, adrenal or other cancers.

Orphagen has identified small molecule antagonists to SF-1 that have the potential to suppress cortisol levels in all Cushing’s patients without serious side effects.

Adrenocortical carcinoma (ACC):
ACC is a rare malignancy with an extremely poor prognosis (5-year overall survival: 37-47%). Complete surgical resection offers hope for long-term survival but surgery is not an option in up to two-thirds of patients because metastasis has usually occurred by the time of diagnosis.

SF-1 is recognized as a potential mechanism-based therapeutic target for control of ACC and an SF-1 antagonist could be used in the treatment of ACC.

Pediatric ACC:
Pediatric ACC is a very rare but aggressive cancer with a long-term survival rate of about 50%. Approximately 60% of children with adrenocortical tumors are diagnosed before the age of four. The SF-1 gene is amplified and SF-1 protein is overexpressed in the vast majority of childhood adrenocortical tumors strongly implicating SF-1 in pediatric adrenocortical tumorigenesis.

Castration resistant prostate cancer (CRPC):
CRPC is the most common cancer in males. Surgery is not an option if the cancer has spread beyond the prostate gland, at which point patients typically receive hormonal therapy, essentially chemical castration. This course of therapy usually fails within two years, resulting in castration resistant prostate cancer (CRPC). Most patients eventually succumb to CRPC, which is the second leading cause of cancer deaths in men.
SF-1 antagonists may: (1) block the adrenal androgens that circumvent chemical castration, and are a primary cause of CRPC; and (2) inhibit synthesis of androgens within the prostate tumor itself, where SF-1 may control induction of enzymes for de novo androgen synthesis in treatment-resistant cancers.

From http://www.orphagen.com/research_cushings.html

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