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Featured researches published by Jérôme Bertherat.


The Journal of Clinical Endocrinology and Metabolism | 2008

Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

Beverly M. K. Biller; Ashley B. Grossman; Paul M. Stewart; Shlomo Melmed; Xavier Bertagna; Jérôme Bertherat; Michael Buchfelder; Annamaria Colao; A.R.M.M. Hermus; Leo J. Hofland; Anne Klibanski; André Lacroix; John Lindsay; John Newell-Price; Lynnette K. Nieman; S. Petersenn; Nicoletta Sonino; Günter K. Stalla; Brooke Swearingen; Mary Lee Vance; John Wass; Marco Boscaro

OBJECTIVE Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushings syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushings syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushings disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushings disease, and 5) management of ectopic ACTH syndrome, Nelsons syndrome, and special patient populations. EVIDENCE Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS ACTH-dependent Cushings syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushings syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushings disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushings syndrome, early diagnosis and prompt therapy are warranted.


Journal of Clinical Oncology | 2005

Genetic Testing in Pheochromocytoma or Functional Paraganglioma

Laurence Amar; Jérôme Bertherat; Eric Baudin; Christiane Ajzenberg; Brigitte Bressac-de Paillerets; Olivier Chabre; Bernard Chamontin; B. Delemer; Sophie Giraud; Arnaud Murat; Patricia Niccoli-Sire; Stéphane Richard; V. Rohmer; Jean-Louis Sadoul; Laurence Strompf; Martin Schlumberger; Xavier Bertagna; Pierre-François Plouin; Xavier Jeunemaitre; Anne-Paule Gimenez-Roqueplo

PURPOSE To assess the yield and the clinical value of systematic screening of susceptibility genes for patients with pheochromocytoma (pheo) or functional paraganglioma (pgl). PATIENTS AND METHODS We studied 314 patients with a pheo or a functional pgl, including 56 patients having a family history and/or a syndromic presentation and 258 patients having an apparently sporadic presentation. Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria. RESULTS We have identified 86 patients (27.4%) with a hereditary tumor. Among the 56 patients with a family/syndromic presentation, 13 have had neurofibromatosis type 1, and germline mutations on the VHL, RET, SDHD, and SDHB genes were present in 16, 15, nine, and three patients, respectively. Among the 258 patients with an apparently sporadic presentation, 30 (11.6%) had a germline mutation (18 patients on SDHB, nine patients on VHL, two patients on SDHD, and one patient on RET). Mutation carriers were younger and more frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, more frequently extra-adrenal, and malignant. CONCLUSION Genetic testing oriented by family/sporadic presentation should be proposed to all patients with pheo or functional pgl. We suggest an algorithm that would allow the confirmation of suspected inherited disease as well as the diagnosis of unexpected inherited disease.


Human Molecular Genetics | 2010

SDHA is a tumor suppressor gene causing paraganglioma

Nelly Burnichon; Jean-Jacques Brière; Rossella Libé; Laure Vescovo; Julie Rivière; Frédérique Tissier; Elodie Jouanno; Xavier Jeunemaitre; Paule Bénit; Alexander Tzagoloff; Pierre Rustin; Jérôme Bertherat; Judith Favier; Anne-Paule Gimenez-Roqueplo

Mitochondrial succinate-coenzyme Q reductase (complex II) consists of four subunits, SDHA, SDHB, SDHC and SDHD. Heterozygous germline mutations in SDHB, SDHC, SDHD and SDHAF2 [encoding for succinate dehydrogenase (SDH) complex assembly factor 2] cause hereditary paragangliomas and pheochromocytomas. Surprisingly, no genetic link between SDHA and paraganglioma/pheochromocytoma syndrome has ever been established. We identified a heterozygous germline SDHA mutation, p.Arg589Trp, in a woman suffering from catecholamine-secreting abdominal paraganglioma. The functionality of the SDHA mutant was assessed by studying SDHA, SDHB, HIF-1alpha and CD34 protein expression using immunohistochemistry and by examining the effect of the mutation in a yeast model. Microarray analyses were performed to study gene expression involved in energy metabolism and hypoxic pathways. We also investigated 202 paragangliomas or pheochromocytomas for loss of heterozygosity (LOH) at the SDHA, SDHB, SDHC and SDHD loci by BAC array comparative genomic hybridization. In vivo and in vitro functional studies demonstrated that the SDHA mutation causes a loss of SDH enzymatic activity in tumor tissue and in the yeast model. Immunohistochemistry and transcriptome analyses established that the SDHA mutation causes pseudo-hypoxia, which leads to a subsequent increase in angiogenesis, as other SDHx gene mutations. LOH was detected at the SDHA locus in the patients tumor but was present in only 4.5% of a large series of paragangliomas and pheochromocytomas. The SDHA gene should be added to the list of genes encoding tricarboxylic acid cycle proteins that act as tumor suppressor genes and can now be considered as a new paraganglioma/pheochromocytoma susceptibility gene.


Cancer Cell | 2013

SDH Mutations Establish a Hypermethylator Phenotype in Paraganglioma

Eric Letouzé; Cosimo Martinelli; Céline Loriot; Nelly Burnichon; Nasséra Abermil; Chris Ottolenghi; Maxime Janin; Mélanie Menara; An Thach Nguyen; Paule Bénit; Alexandre Buffet; Charles Marcaillou; Jérôme Bertherat; Laurence Amar; Pierre Rustin; Aurélien de Reyniès; Anne-Paule Gimenez-Roqueplo; Judith Favier

Paragangliomas are neuroendocrine tumors frequently associated with mutations in RET, NF1, VHL, and succinate dehydrogenase (SDHx) genes. Methylome analysis of a large paraganglioma cohort identified three stable clusters, associated with distinct clinical features and mutational status. SDHx-related tumors displayed a hypermethylator phenotype, associated with downregulation of key genes involved in neuroendocrine differentiation. Succinate accumulation in SDH-deficient mouse chromaffin cells led to DNA hypermethylation by inhibition of 2-OG-dependent histone and DNA demethylases and established a migratory phenotype reversed by decitabine treatment. Epigenetic silencing was particularly severe in SDHB-mutated tumors, potentially explaining their malignancy. Finally, inactivating FH mutations were identified in the only hypermethylated tumor without SDHx mutations. These findings emphasize the interplay between the Krebs cycle, epigenomic changes, and cancer.


Lancet Oncology | 2009

An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis.

Francien H. van Nederveen; José Gaal; Judith Favier; Esther Korpershoek; Rogier A. Oldenburg; Elly M C A de Bruyn; Hein Sleddens; Pieter Derkx; Julie Rivière; Hilde Dannenberg; Bart-Jeroen Petri; Paul Komminoth; Karel Pacak; Wim C. J. Hop; Patrick J. Pollard; Massimo Mannelli; Jean-Pierre Bayley; Aurel Perren; Stephan Niemann; A.A.J. Verhofstad; Adriaan P. de Bruïne; Eamonn R. Maher; Frédérique Tissier; Tchao Meatchi; Cécile Badoual; Jérôme Bertherat; Laurence Amar; Despoina Alataki; Eric Van Marck; Francesco Ferraù

BACKGROUND Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma-paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma-paraganglioma syndrome is often unrecognised, although 10-30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series. METHODS Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. FINDINGS SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87-100) and 84% (60-97), respectively. INTERPRETATION Phaeochromocytoma-paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma-paraganglioma syndrome. FUNDING The Netherlands Organisation for Scientific Research, Dutch Cancer Society, Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and a PHRC grant COMETE 3 for the COMETE network.


Cancer Research | 2005

Mutations of β-Catenin in Adrenocortical Tumors: Activation of the Wnt Signaling Pathway Is a Frequent Event in both Benign and Malignant Adrenocortical Tumors

Frédérique Tissier; Catherine Cavard; Lionel Groussin; Karine Perlemoine; Gwladys Fumey; Anne-Marie Hagneré; F. René-Corail; E. Jullian; Christine Gicquel; Xavier Bertagna; Marie-Cécile Vacher-Lavenu; Christine Perret; Jérôme Bertherat

Adrenocortical cancer is a rare cancer with a very poor prognosis. The genetic alterations identified to date in adrenocortical tumors are limited. Activating mutations of the Wnt signaling pathway have been observed in more frequent cancers, particularly digestive tract tumors. We investigated whether Wnt pathway activation is involved in adrenocortical tumorigenesis. In a series of 39 adrenocortical tumors, immunohistochemistry revealed abnormal cytoplasmic and/or nuclear accumulation of beta-catenin in 10 of 26 adrenocortical adenomas and in 11 of 13 adrenocortical carcinomas. An activating somatic mutation of the beta-catenin gene was shown in 7 of 26 adrenocortical adenomas and in 4 of 13 adrenocortical carcinomas; these mutations were observed only in adrenocortical tumors with abnormal beta-catenin accumulation and most were point mutations altering the Ser45 of exon 3 (in the consensus GSK3-beta/CK1 phosphorylation site). Functional studies showed that the activating Ser45 beta-catenin mutation found in the adrenocortical cancer H295R cell line leads to constitutive activation of T-cell factor-dependent transcription. This is the first molecular defect to be reported with the same prevalence in both benign (27%) and malignant (31%) adrenocortical tumors. beta-Catenin mutations are also the most frequent genetic defect currently known in adrenocortical adenomas. In adrenocortical adenomas, beta-catenin alterations are more frequent in nonfunctioning tumors, suggesting that beta-catenin pathway activation might be mostly involved in the development of nonsecreting adrenocortical adenomas and adrenocortical carcinomas. The very frequent and substantial accumulation of beta-catenin in adrenocortical carcinomas suggests that other alterations might also be involved. This finding may contribute to new therapeutic approaches targeting the Wnt pathway in malignant adrenocortical tumors, for which limited medical therapy is available.


The Journal of Clinical Endocrinology and Metabolism | 2009

Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial

Marco Boscaro; W. H. Ludlam; B. Atkinson; J. E. Glusman; Stephan Petersenn; Martin Reincke; Peter J. Snyder; Antoine Tabarin; Beverly M. K. Biller; James W. Findling; Shlomo Melmed; C. H. Darby; K. Hu; Yibin Wang; Pamela U. Freda; Ashley B. Grossman; Lawrence A. Frohman; Jérôme Bertherat

CONTEXT There is currently no medical therapy for Cushings disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder. OBJECTIVE Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushings disease. DESIGN We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study. PATIENTS Thirty-nine patients with either de novo Cushings disease who were candidates for pituitary surgery or with persistent or recurrent Cushings disease after surgery without having received prior pituitary irradiation. INTERVENTION Patients self-administered sc pasireotide 600 microg twice daily for 15 d. MAIN OUTCOME MEASURE Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure. RESULTS Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders. CONCLUSIONS Pasireotide produced a decrease in UFC levels in 76% of patients with Cushings disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.


Nature Genetics | 2006

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 ( PDE11A ) in individuals with adrenocortical hyperplasia

Anelia Horvath; Sosipatros A. Boikos; Christoforos Giatzakis; Audrey Robinson-White; Lionel Groussin; Kurt J. Griffin; Erica V. Stein; Elizabeth Levine; Georgia Delimpasi; Hui Pin Hsiao; Meg Keil; Sarah L. Heyerdahl; Ludmila Matyakhina; Rossella Libé; Amato Fratticci; Lawrence S. Kirschner; Kevin Cramer; Rolf C. Gaillard; Xavier Bertagna; J. Aidan Carney; Jérôme Bertherat; Ioannis Bossis; Constantine A. Stratakis

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31–2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31–2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.


Journal of Clinical Oncology | 2009

Gene Expression Profiling Reveals a New Classification of Adrenocortical Tumors and Identifies Molecular Predictors of Malignancy and Survival

Aurélien de Reyniès; Guillaume Assié; David S. Rickman; Frédérique Tissier; Lionel Groussin; F. René-Corail; Bertrand Dousset; Xavier Bertagna; Eric Clauser; Jérôme Bertherat

PURPOSE Adrenocortical tumors, especially cancers, remain challenging both for their diagnosis and prognosis assessment. The aim of this article is to identify molecular predictors of malignancy and of survival. PATIENTS AND METHODS One hundred fifty-three unilateral adrenocortical tumors were studied by microarray (n = 92) or reverse transcription quantitative polymerase chain reaction (n = 148). A two-gene predictor of malignancy was built using the disease-free survival as the end point in a training cohort (n = 47), then validated in an independent validation cohort (n = 104). The best candidate genes were selected using Cox models, and the best gene combination was validated using the log-rank test. Similarly, for malignant tumors, a two-gene predictor of survival was built using the overall survival as the end point in a training cohort (n = 23), then tested in an independent validation cohort (n = 35). RESULTS Unsupervised clustering analysis discriminated robustly the malignant and benign tumors, and identified two groups of malignant tumors with very different outcome. The combined expression of DLG7 and PINK1 was the best predictor of disease-free survival (log-rank P approximately 10(-12)), could overcome the uncertainties of intermediate pathological Weiss scores, and remained significant after adjustment to the Weiss score (P < 1.3 x 10(-2)). Among the malignant tumors, the combined expression of BUB1B and PINK1 was the best predictor of overall survival (P < 2 x 10(-6)), and remained significant after adjusting for MacFarlane staging (P < .005). CONCLUSION Gene expression analysis unravels two distinct groups of adrenocortical carcinomas. The molecular predictors of malignancy and of survival are reliable and provide valuable independent information in addition to pathology and tumor staging. These original tools should provide important improvements for adrenal tumors management.


Nature Genetics | 2014

Integrated genomic characterization of adrenocortical carcinoma

Guillaume Assié; Eric Letouzé; Martin Fassnacht; Anne Jouinot; Windy Luscap; Olivia Barreau; Hanin Omeiri; S. Rodriguez; Karine Perlemoine; F. René-Corail; Nabila Elarouci; Silviu Sbiera; Matthias Kroiss; Bruno Allolio; Jens Waldmann; Marcus Quinkler; Massimo Mannelli; Franco Mantero; Thomas G. Papathomas; Ronald R. de Krijger; Antoine Tabarin; V. Kerlan; Eric Baudin; Frédérique Tissier; Bertrand Dousset; Lionel Groussin; Laurence Amar; Eric Clauser; Xavier Bertagna; Bruno Ragazzon

Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.

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Lionel Groussin

Paris Descartes University

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Guillaume Assié

Paris Descartes University

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Rossella Libé

Paris Descartes University

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Bruno Ragazzon

Paris Descartes University

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Xavier Bertagna

French Institute of Health and Medical Research

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Bertrand Dousset

Paris Descartes University

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Karine Perlemoine

Paris Descartes University

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Olivier Chabre

Centre Hospitalier Universitaire de Grenoble

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