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1. Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function

Author: Denis Dacheux, Guillaume Martinez, Christine E Broster Reix, Julie Beurois, Patrick Lores, Magamba Tounkara, Jean-William Dupuy, Derrick Roy Robinson, Corinne Loeuillet, Emeline Lambert, Zeina Wehbe, Jessica Escoffier, Amir Amiri-Yekta, Abbas Daneshipour, Seyedeh-Hanieh Hosseini, Raoudha Zouari, Selima Fourati Ben Mustapha, Lazhar Halouani, Xiaohui Jiang, Ying Shen, Chunyu Liu, Nicolas Thierry-Mieg, Amandine Septier, Marie Bidart, Véronique Satre, Caroline Cazin, Zine Eddine Kherraf, Christophe Arnoult, Pierre F Ray, Aminata Toure, Mélanie Bonhivers, and Charles Coutton
Subjects: Trypanosoma brucei, male infertility, asthenoteratozoospermia, sperm flagellum, DNAH1, TTC29, Medicine, Science, Biology (General), QH301-705.5
Abstract: Male infertility is common and complex, presenting a wide range of heterogeneous phenotypes. Although about 50% of cases are estimated to have a genetic component, the underlying cause often remains undetermined. Here, from whole-exome sequencing on samples from 168 infertile men with asthenoteratozoospermia due to severe sperm flagellum, we identified homozygous ZMYND12 variants in four unrelated patients. In sperm cells from these individuals, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66, and TTC29. Axonemal localization of ZMYND12 ortholog TbTAX-1 was confirmed using the Trypanosoma brucei model. RNAi knock-down of TbTAX-1 dramatically affected flagellar motility, with a phenotype similar to the sperm from men bearing homozygous ZMYND12 variants. Co-immunoprecipitation and ultrastructure expansion microscopy in T. brucei revealed TbTAX-1 to form a complex with TTC29. Comparative proteomics with samples from Trypanosoma and Ttc29 KO mice identified a third member of this complex: DNAH1. The data presented revealed that ZMYND12 is part of the same axonemal complex as TTC29 and DNAH1, which is critical for flagellum function and assembly in humans, and Trypanosoma. ZMYND12 is thus a new asthenoteratozoospermia-associated gene, bi-allelic variants of which cause severe flagellum malformations and primary male infertility.
Published: 2023
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2. Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma

Author: Anne Jouinot, Juliane Lippert, Martin Fassnacht, Bruno de La Villeon, Amandine Septier, Mario Neou, Karine Perlemoine, Silke Appenzeller, Mathilde Sibony, Sébastien Gaujoux, Bertrand Dousset, Rossella Libe, Lionel Groussin, Cristina L Ronchi, Guillaume Assié, and Jérôme Bertherat
Subjects: adrenocortical carcinoma, intratumor heterogeneity, methylation, chromosome alterations, somatic mutations, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific m olecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level. Methods: Two different tissue samples (primary tumor, local recurrence o r metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated i n frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12). Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were ‘Noisy’ (numerous and anarch ic alterations) in 8/14 and ‘Chromosomal’ (extended patterns of loss of heterozygo sity) in 5/14 of the study samples. For these profiles, no intratumor heterogenei ty was observed. Methylation profiles were hypermethylated in 5/12 and non-hyperm ethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation p rofiles was observed in 2/12 patients (17%). Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chro mosome alteration profile seem rather stable and might be more robust for the prog nostic assessment.
Published: 2020
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3. Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia.

Author: Laura Bousset, Amandine Septier, Julio Bunay, Allison Voisin, Rachel Guiton, Christelle Damon-Soubeyrant, Yoan Renaud, Angélique De Haze, Vincent Sapin, Anne Fogli, Amandine Rambur, Cyrille De Joussineau, Ayhan Kocer, Amalia Trousson, Joëlle Henry-Berger, Marcus Höring, Gerhard Liebisch, Silke Matysik, Jean-Marc A Lobaccaro, Laurent Morel, and Silvère Baron
Subjects: Biology (General), QH301-705.5
Abstract: Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.
Published: 2020
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4. RETRACTED ARTICLE: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer

Author: Anthony Alioui, Julie Dufour, Valerio Leoni, Anke Loregger, Martina Moeton, Luigi Iuliano, Chiara Zerbinati, Amandine Septier, Pierre Val, Allan Fouache, Vincenzo Russo, David H. Volle, Jean-Marc A. Lobaccaro, Noam Zelcer, and Silvère Baron
Subjects: Science
Abstract: Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors.
Published: 2017
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5. Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer

Author: Anthony Alioui, Julie Dufour, Valerio Leoni, Anke Loregger, Martina Moeton, Luigi Iuliano, Chiara Zerbinati, Amandine Septier, Pierre Val, Allan Fouache, Vincenzo Russo, David H. Volle, Jean-Marc A. Lobaccaro, Noam Zelcer, and Silvère Baron
Subjects: Science
Abstract: This paper has been retracted at the request of the authors.
Published: 2018
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6. Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia

Author: Zine-Eddine Kherraf, Caroline Cazin, Amine Bouker, Selima Fourati Ben Mustapha, Sylviane Hennebicq, Amandine Septier, Charles Coutton, Laure Raymond, Marc Nouchy, Nicolas Thierry-Mieg, Raoudha Zouari, Christophe Arnoult, and Pierre F. Ray
Subjects: DNA-Binding Proteins, Male, Sperm Retrieval, Testis, Exome Sequencing, DNA Helicases, Genetics, Humans, Article, Genetics (clinical), Azoospermia
Abstract: Non-obstructive azoospermia (NOA) is a severe and frequent cause of male infertility, often treated by testicular sperm extraction followed by intracytoplasmic sperm injection. The aim of this study is to improve the genetic diagnosis of NOA, by identifying new genes involved in human NOA and to better assess the chances of successful sperm extraction according to the individual’s genotype. Exome sequencing was performed on 96 NOA-affected individuals negative for routine genetic tests. Bioinformatics analysis was limited to a panel of 151 genes selected as known causal or candidate genes for NOA. Only highly deleterious homozygous or hemizygous variants were retained as candidates. A likely causal defect was identified in 16 genes in a total of 22 individuals (23%). Six genes had not been described in man (DDX25, HENMT1, MCMDC2, MSH5, REC8, TDRKH) and 10 were previously reported (C14orf39, DMC1, FANCM, GCNA, HFM1, MCM8, MEIOB, PDHA2, TDRD9, TERB1). Seven individuals had defects in genes from piwi or DNA repair pathways, three in genes involved in post-meiotic maturation, and 12 in meiotic processes. Interestingly, all individuals with defects in meiotic genes had an unsuccessful sperm retrieval, indicating that genetic diagnosis prior to TESE could help identify individuals with low or null chances of successful sperm retrieval and thus avoid unsuccessful surgeries.
Published: 2022
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7. Whole blood methylome-derived features to discriminate endocrine hypertension

Author: Roberta Armignacco, Parminder S. Reel, Smarti Reel, Anne Jouinot, Amandine Septier, Cassandra Gaspar, Karine Perlemoine, Casper K. Larsen, Lucas Bouys, Leah Braun, Anna Riester, Matthias Kroiss, Fidéline Bonnet-Serrano, Laurence Amar, Anne Blanchard, Anne-Paule Gimenez-Roqueplo, Aleksander Prejbisz, Andrzej Januszewicz, Piotr Dobrowolski, Eleanor Davies, Scott M. MacKenzie, Gian Paolo Rossi, Livia Lenzini, Filippo Ceccato, Carla Scaroni, Paolo Mulatero, Tracy A. Williams, Alessio Pecori, Silvia Monticone, Felix Beuschlein, Martin Reincke, Maria-Christina Zennaro, Jérôme Bertherat, Emily Jefferson, Guillaume Assié, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Dundee, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ludwig-Maximilians University [Munich] (LMU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institute of Cardiology (WARSAW - Cardiology), Institute of Cardiology, University of Glasgow, Università degli Studi di Padova = University of Padua (Unipd), Università degli studi di Torino = University of Turin (UNITO), Universität Zürich [Zürich] = University of Zurich (UZH), and BRUNEL, Nadège
Subjects: Circulating biomarker, Endocrine hypertension, Whole blood methylome, Adrenal Gland Neoplasms, Pheochromocytoma, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, DNA Methylation, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Epigenome, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Hypertension, Genetics, Humans, Molecular Biology, Genetics (clinical), Biomarkers, Developmental Biology
Abstract: Background Arterial hypertension represents a worldwide health burden and a major risk factor for cardiovascular morbidity and mortality. Hypertension can be primary (primary hypertension, PHT), or secondary to endocrine disorders (endocrine hypertension, EHT), such as Cushing's syndrome (CS), primary aldosteronism (PA), and pheochromocytoma/paraganglioma (PPGL). Diagnosis of EHT is currently based on hormone assays. Efficient detection remains challenging, but is crucial to properly orientate patients for diagnostic confirmation and specific treatment. More accurate biomarkers would help in the diagnostic pathway. We hypothesized that each type of endocrine hypertension could be associated with a specific blood DNA methylation signature, which could be used for disease discrimination. To identify such markers, we aimed at exploring the methylome profiles in a cohort of 255 patients with hypertension, either PHT (n = 42) or EHT (n = 213), and at identifying specific discriminating signatures using machine learning approaches. Results Unsupervised classification of samples showed discrimination of PHT from EHT. CS patients clustered separately from all other patients, whereas PA and PPGL showed an overall overlap. Global methylation was decreased in the CS group compared to PHT. Supervised comparison with PHT identified differentially methylated CpG sites for each type of endocrine hypertension, showing a diffuse genomic location. Among the most differentially methylated genes, FKBP5 was identified in the CS group. Using four different machine learning methods—Lasso (Least Absolute Shrinkage and Selection Operator), Logistic Regression, Random Forest, and Support Vector Machine—predictive models for each type of endocrine hypertension were built on training cohorts (80% of samples for each hypertension type) and estimated on validation cohorts (20% of samples for each hypertension type). Balanced accuracies ranged from 0.55 to 0.74 for predicting EHT, 0.85 to 0.95 for predicting CS, 0.66 to 0.88 for predicting PA, and 0.70 to 0.83 for predicting PPGL. Conclusions The blood DNA methylome can discriminate endocrine hypertension, with methylation signatures for each type of endocrine disorder.
Published: 2022
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8. Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma

Author: Anne Jouinot, Juliane Lippert, Mathilde Sibony, Florian Violon, Lindsay Jeanpierre, Daniel De Murat, Roberta Armignacco, Amandine Septier, Karine Perlemoine, Franck Letourneur, Brigitte Izac, Bruno Ragazzon, Karen Leroy, Eric Pasmant, Marie-Odile North, Sébastien Gaujoux, Bertrand Dousset, Lionel Groussin, Rossella Libe, Benoit Terris, Martin Fassnacht, Cristina L Ronchi, Jérôme Bertherat, and Guillaume Assie
Subjects: Paraffin Embedding, Tissue Fixation, Endocrinology, Diabetes and Metabolism, Gene Expression Profiling, General Medicine, Prognosis, Adrenal Cortex Neoplasms, Endocrinology, Paraffin, Formaldehyde, Adrenocortical Carcinoma, Humans, RNA, Transcriptome, Retrospective Studies
Abstract: Design Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas ‘C2’ from carcinomas, and identify two groups of carcinomas ‘C1A’ and ‘C1B’, of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3’-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants. Methods We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3’ transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA). Results In the training cohort, unsupervised clustering identified three groups: ‘C1A’ aggressive carcinomas (n = 28, 29%), ‘C1B’ more indolent carcinomas (n = 28, 29%), and ‘C2’ adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in ‘C1A’ (n = 26) and 100% in ‘C1B’ (n = 10), P = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in ‘C1B’. Conclusions The 3’ RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.
Published: 2021

9. Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

Author: Anne-Marie Lefrançois-Martinez, Amandine Septier, Amanda Swain, Jean-Christophe Pointud, Constantine A. Stratakis, Fabio R. Faucz, Florian Guillou, James Wilmouth, Antoine-Guy Lopez, Adrien Levasseur, Ingrid Plotton, Cyril Djari, Seppo Vainio, Crystal Kamilaris, Isabelle Sahut-Barnola, Hervé Lefebvre, Damien Dufour, Pierre Val, Nathanaëlle Montanier, Antoine Martinez, Igor Tauveron, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Hospices Civils de Lyon (HCL), CHU Clermont-Ferrand, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The institute of cancer research [London], and University of Oulu
Subjects: Male, Somatic cell, [SDV]Life Sciences [q-bio], Apoptosis, Mice, 0302 clinical medicine, Wnt4 Protein, Testis, WNT4, Genes, Tumor Suppressor, PRKAR1A, ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, Mice, Knockout, 0303 health sciences, Pigmentation, General Medicine, Seminiferous Tubules, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Sertoli cell, Phenotype, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Research Article, Cell type, Stromal cell, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Paracrine signalling, Testicular Neoplasms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Paracrine Communication, medicine, Animals, Humans, Carney Complex, Carney complex, 030304 developmental biology, Sertoli Cells, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Cyclic AMP-Dependent Protein Kinases, Disease Models, Animal, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Mutation, Cancer research, Transcriptome
Abstract: International audience; Large-cell calcifying Sertoli cell tumors (LCCSCTs) are among the most frequent lesions occurring in male Carney complex (CNC) patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A, leading to unrepressed PKA activity, LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the induction of CNC testis lesions. We demonstrate that the Prkar1a mutation was required in both stromal and Sertoli cells for the occurrence of LCCSCTs. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to the understanding of human LCCSCT pathogenesis and demonstrated PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in a mouse model and in human CNC testes.
Published: 2021
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10. Identification of glucocorticoid-related molecular signature by whole blood methylome analysis

Author: Roberta Armignacco, Anne Jouinot, Lucas Bouys, Amandine Septier, Thomas Lartigue, Mario Neou, Cassandra Gaspar, Karine Perlemoine, Leah Braun, Anna Riester, Fidéline Bonnet-Serrano, Anne Blanchard, Laurence Amar, Carla Scaroni, Filippo Ceccato, Gian Paolo Rossi, Tracy Ann Williams, Casper K Larsen, Stéphanie Allassonnière, Maria-Christina Zennaro, Felix Beuschlein, Martin Reincke, Jérôme Bertherat, Guillaume Assié, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Mathématiques Appliquées - Ecole Polytechnique (CMAP), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ludwig Maximilian University [Munich] (LMU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC AP-HP (hegp Ex-Broussais)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d'HYPERVASC [CHU HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Azienda Ospedaliera di Padova, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Department of Medical Sciences [Turin, Italy] (DMS), Università degli studi di Torino = University of Turin (UNITO), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Service de Génétique [CHU HEGP], Universitätsspital Zürich (USZ), Service d'Endocrinologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), European Project: 678304,H2020 ERC,ERC-2015-STG,LEASP(2016), European Project: 666992,H2020 Pilier Societal Challenges,H2020-PHC-2015-two-stage,EuroPOND(2016), European Project: 826421,TVB-Cloud (2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University Hospital of Padua, University of Turin, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), and University of Zurich
Subjects: Adult, Male, Adolescent, Hydrocortisone, Endocrinology, Diabetes and Metabolism, 10265 Clinic for Endocrinology and Diabetology, 610 Medicine & health, Tacrolimus Binding Proteins, Adrenal Insufficiency, Aged, Biomarkers, CpG Islands, Cushing Syndrome, DNA, DNA Methylation, Epigenome, Female, Glucocorticoids, Humans, Leukocytes, Middle Aged, Saliva, Endocrinology, Circulating biomarker, Whole blood methylome, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 1310 Endocrinology, 2712 Endocrinology, Diabetes and Metabolism, Cushing’s syndrome, Clinical Study
Abstract: Objective Cushing’s syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing’s syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing’s syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers. Design We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing’s syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation. Methods Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850 000 CpG sites). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features. Results Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing’s syndrome correction. In Cushing’s syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts. Conclusions Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assessment of glucocorticoid action beyond hormone assays.
Published: 2021
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11. Le profil de méthylome du sang total comme biomarqueur de l’excès des glucocorticoïdes

Author: Laurence Amar, Fideline Bonnet-Serrano, Anna Riester, Roberta Armignacco, Karine Perlemoine, Jérôme Bertherat, Leah T. Braun, Mario Neou, Guillaume Assié, Martin Reincke, Filippo Ceccato, Lucas Bouys, Anne Blanchard, Casper K Larsen, Maria-Christina Zennaro, Tracy Ann Williams, Anne Jouinot, F Beuschlein, Amandine Septier, Gian Paolo Rossi, Carla Scaroni, Stéphanie Allassonnière, Thomas Lartigue, Cassandra Gaspar, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Mathématiques Appliquées - Ecole Polytechnique (CMAP), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ludwig Maximilian University [Munich] (LMU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC AP-HP (hegp Ex-Broussais)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Azienda Ospedaliera di Padova, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Università degli studi di Torino = University of Turin (UNITO), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Universitätsspital Zürich (USZ), Université Paris Cité (UPCité), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Université Paris Cité (UPC), Université Paris Cité - UFR Médecine Paris Centre [Santé] (UPC Médecine Paris Centre), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University Hospital of Padua, Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Turin, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Université de Paris (UP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and University of Turin
Subjects: 03 medical and health sciences, 0302 clinical medicine, Endocrinology, 030220 oncology & carcinogenesis, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, General Medicine, ComputingMilieux_MISCELLANEOUS
Abstract: Les dosages hormonaux sur lesquels s’appuie le diagnostic d’hypercortisolisme ne refletent pas les effets individuels d’impregnation en glucocorticoides. Pour identifier des biomarqueurs specifiques, le methylome du sang total a ete analyse (puce Illumina-850 K CpGs) dans 94 echantillons de 47 patients avec different statut cortisolique -syndrome de Cushing, eucortisolisme, insuffisance surrenalienne. Le profil de methylation des plus variable CpGs (ecart type) discrimine les echantillons selon leur statut, avec une marque d’hypomethylation dans les Cushing. Cette marque montre une cinetique de modification dans le temps, avec une recuperation du niveau de methylation plusieurs mois apres traitement. Un groupe de 29 CpGs, selectionnes par regression penalisee, discrimine le statut de Cushing dans un sous-cohorte d’entrainement de 60 echantillons (30 Cushing et 30 eucortisolisme/insuffisances surrenaliennes). La performance de ce predicteur est validee dans le reste des echantillons (n = 34 ; OR : 1,58) et dans une deuxieme cohorte de validation independante de 91 echantillons -dont 26 Cushing et 65 eucortisolisme (OR : 1,10). Le niveau de methylation d’un seul des 29 CpGs, associe au promoteur du gene FKBP5, recapitule la discrimination par statut cortisolique dans les deux cohortes. Le taux de neutrophiles infere a partir du methylome s’associe, comme attendu, au statut cortisolique. Cependant, dans un modele d’analyse multivarie, le predicteur de 29 CpGs reste fortement significatif quand combine au taux de neutrophiles (p Conclusion le methylome reflete l’impregnation en glucocorticoides. Perspectives optimiser le methylome pour la routine, l’evaluer dans les hypercortisolismes a minima, et le tester pour predire les complications de l’hypercortisolisme.
Published: 2021
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12. EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness

Author: Bruno Ragazzon, Jean-Christophe Pointud, Houda Tabbal, Pierre Val, Igor Tauveron, Coralie Drelon, M. Batisse-Lignier, Cyril Djari, Stéphanie Rodriguez, Anne-Marie Lefrançois-Martinez, Amandine Septier, Jérôme Bertherat, Guillaume Assié, Isabelle Sahut-Barnola, Mickael Mathieu, Antoine Martinez, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Clermont-Ferrand, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Cancer Research, Adenosine, Indoles, Cell Cycle Proteins, MESH: Adrenal Cortex Neoplasms, MESH: Mice, Knockout, MESH: Proportional Hazards Models, MESH: Adrenocortical Carcinoma, 0302 clinical medicine, Gene expression, Adrenocortical Carcinoma, E2F1, MESH: Animals, Mice, Knockout, MESH: Chromatin Immunoprecipitation, MESH: Indoles, Regulation of gene expression, biology, EZH2, MESH: Gene Expression Regulation, Neoplastic, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Ribonucleoside Diphosphate Reductase, 3. Good health, Gene Expression Regulation, Neoplastic, Securin, MESH: E2F1 Transcription Factor, Histone, Oncology, 030220 oncology & carcinogenesis, MESH: Computational Biology, Chromatin Immunoprecipitation, Ribonucleoside Diphosphate Reductase, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Article, Adrenal tumours, MESH: Multivariate Analysis, 03 medical and health sciences, MESH: Cell Cycle Proteins, Cancer epigenetics, MESH: Cell Proliferation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Enhancer of Zeste Homolog 2 Protein, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Transcription factor, Cell Proliferation, Proportional Hazards Models, MESH: Humans, Cell growth, Computational Biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Adenosine, Adrenal Cortex Neoplasms, MESH: Securin, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Multivariate Analysis, biology.protein, Cancer research, Chromatin immunoprecipitation, E2F1 Transcription Factor
Abstract: International audience; BACKGROUND: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. METHODS: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. RESULTS: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. CONCLUSIONS: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness. British Journal of Cancer https://doi.org/10.1038/s41416-019-0538-y BACKGROUND Adrenocortical carcinomas (ACC) are endocrine malignancies associated with dismal prognosis. At diagnosis, 80% of patients present metastases reducing the 5 years survival rate below 30% for most series.
Published: 2019
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13. PDE11A4 (Phosphodiesterase 11 A4) is a modulator of the primary bilateral macronodular adrenal hyperplasia (PBMAH) phenotype: genotype/phenotype analysis of a cohort of 354 patients analysed by next-generation sequencing (NGS)

Author: Bruno Ragazzon, Barisson Villares Fragoso Maria Candida, Marie-Christine, Matthias Kroiss, Mario Neou, Patricia Vaduva, RossellaLibe, Faucz Fabio, Amandine Septier, Françoise Borson-Chazot, Jérôme Bertherat, Guillaume Assié, Giannone Gaetan, Antoine Tabarin, Victor Heurtier, Bouys Lucas, Philippe Chanson, Stratakis Constantine, Vaczlavik Anna, and Isadora Pontes Cavalcante
Subjects: business.industry, Macronodular Adrenal Hyperplasia, Cohort, Cancer research, Phenotype genotype, Phosphodiesterase, Medicine, business, Phenotype, DNA sequencing
Published: 2021
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14. Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors

Author: Bertrand Dousset, Marc Diedisheim, Anne Jouinot, Etienne Larger, Guillaume Cadiot, Solène Dermine, Jérôme Bertherat, Benoit Terris, Romain Coriat, Guillaume Assié, Amandine Septier, Sébastien Gaujoux, Raphael Scharfmann, YOU, Sylvaine, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, duodenopancreatic neuroendocrine tumors, [SDV]Life Sciences [q-bio], RNA-Seq, Disease, Neuroendocrine tumors, Genomic screening, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Text mining, FGA, Internal medicine, medicine, Multiple Endocrine Neoplasia Type 1, Humans, Stage (cooking), PDX1, business.industry, dedifferentiation, medicine.disease, Prognosis, [SDV] Life Sciences [q-bio], Pancreatic Neoplasms, Neuroendocrine Tumors, 030104 developmental biology, 030220 oncology & carcinogenesis, Insulinoma, ARX, business
Abstract: Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular updates changing the definition of classes. Genomic screening may provide more objective classes and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcomes (log-rank P < 0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the topmost expressed liver genes. FGA expression was associated with disease-free survival (HR = 1.13, P = 0.005) and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.
Published: 2021
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15. PKA drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

Author: Amanda Swain, Ag Lopez, A. Levasseur, Amandine Septier, Igor Tauveron, Ingrid Plotton, D. Dufour, Florian Guillou, Am Lefrançois-Martinez, A. Martinez, Isabelle Sahut-Barnola, Hervé Lefebvre, Cyril Djari, Fr Faucz, J. Wilmouth, Jc Pointud, Pierre Val, Nathanaëlle Montanier, C. A. Stratakis, Seppo Vainio, Crystal Kamilaris, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), CHU Clermont-Ferrand, National Institutes of Health [Bethesda] (NIH), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The institute of cancer research [London], University of Oulu, Martinez, Antoine, Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Cell type, Stromal cell, Somatic cell, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], WNT4, medicine, Carney complex, PRKAR1A, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Sertoli cell, medicine.disease, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, medicine.anatomical_structure, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030220 oncology & carcinogenesis, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract: Large Cell Calcifying Sertoli Cell Tumors (LCCSCTs) are among the most frequent lesions occurring in Carney complex (CNC) male patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressorPRKAR1Aleading to unrepressed PKA activity, the LCCSCT pathogenesis and origin remain elusive. Mouse models targetingPrkar1ainactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the CNC testis lesion induction. We demonstrate thatPrkar1amutation is required in both stromal and Sertoli cells for the occurrence of LCCSCT. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to understand the human LCCSCT pathogenesis and demonstrated unprecedented PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in mouse model and human CNC testes.
Published: 2021

16. Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player

Author: Ségolène Veau, Gilles Schuler, Aline Papaxanthos, Julien Bessonnat, Marine Poulain, H. Lejeune, Laurent Pasquier, Rosalie Cabry, Raoudha Zouari, Amandine Septier, Flore Mietton, Myriam Chaabouni, Vincent Achard, Zine-Eddine Kherraf, Charles Coutton, Antoine Clergeau, Dominique Lauton, Christophe Sifer, Béatrice Dorphin, Catherine Guillemain, Mahmoud Kharouf, Tristan Celse, Sebti Benbouhadja, Nathalie Sermondade, Selima Fourati Ben Mustapha, Pierre F. Ray, Delphine Martinez, Bernard Foliguet, Julie Beurois, Valérie Mitchell, Guillaume Martinez, Abdelali Zoghmar, Véronique Satre, Ahmed Chargui, Gérard Tachdjian, Cynthia Frapsauce, Chema Triki, Sylviane Hennebicq, Jacques Puechberty, Caroline Cazin, Christophe Arnoult, Nicolas Thierry-Mieg, Lionel Mery, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Biologie Computationnelle et Modélisation (TIMC-BCM ), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service Endocrinologie - Diabétologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Polyclinique les Jasmins [Tunis], CHU Ibn Rochd [Casablanca], Service d'Histologie-Embryologie, Biologie de la Reproduction (CECOS Paris Cochin), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Laboratoire d’Aide Médicale à la Procréation [CH Alpes-Léman] (AMP 74), Centre AMP 74 [Contamine-sur-Arve]-Centre Hospitalier Alpes-Léman - CHAL, Institut Jean Lamour (IJL), Université de Lorraine (UL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hôpital Jean Verdier [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hospices Civils de Lyon (HCL), Hôpital Arnaud de Villeneuve [CHRU Montpellier], CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Hôpital Foch [Suresnes], Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de l'Environnement Industriel et des Risques, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance Publique - Hôpitaux de Marseille (APHM), Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences, CR Inserm U1209, CNRS UMR5309, University Grenoble Alpes, Team « Génétique, Épigénétique et Thérapies de l'infertilité », Grenoble, France., CHU Grenoble Alpes, UM de GI-DPI, 38000 Grenoble, France, Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Grenoble, UM de Génétique Chromosomique, Biologie Computationnelle et Mathématique (TIMC-BCM ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC ), IMAG-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-IMAG-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Centre clinicobiologique d’AMP, pôle femmes–Parents-Enfants, hôpital de La Conception, AP–HM, 147, boulevard Baille, 13005 Marseille, France, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Obstetrics and Gynecology, University Hospital Bordeaux, Bordeaux, France., Partenaires INRAE, Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University Hospital of Montpellier, Service d'histologie, embryologie et cytogénétique [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], CH Sallanches, Service de Génétique [CHU Montpellier] (Hôpital Arnaud de Villeneuve), Hôpital Arnaud de Villeneuve-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, Service Gynécologie-Obstétrique et Médecine de la reproduction [Hôpital Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Bretonneau, CHU Lille, Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UMR237-Aix Marseille Université (AMU)-Avignon Université (AU), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, and Centre Hospitalier Alpes-Léman - CHAL -Centre AMP 74 [Contamine-sur-Arve]
Subjects: Male, Candidate gene, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Teratozoospermia, 03 medical and health sciences, symbols.namesake, Exome Sequencing, Genetics, Humans, Genetic Testing, Acrosome, Gene, Genetic Association Studies, Infertility, Male, Genetics (clinical), Globozoospermia, Loss function, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Sanger sequencing, 0303 health sciences, Homozygote, 030305 genetics & heredity, Membrane Proteins, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Spermatozoa, Phenotype, Human genetics, 3. Good health, Testicular Hormones, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, symbols, Gene Deletion
Abstract: International audience; Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.
Published: 2021
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17. Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia

Author: Allison Voisin, Silvère Baron, Amandine Septier, Jean-Marc A. Lobaccaro, Ayhan Kocer, Gerhard Liebisch, Silke Matysik, Laura Bousset, Joelle Henry-Berger, Christelle Damon-Soubeyrant, Amandine Rambur, Vincent Sapin, Laurent Morel, Cyrille de Joussineau, Yoan Renaud, Julio Buñay, Amalia Trousson, Angélique De Haze, Marcus Höring, Rachel Guiton, Anne Fogli, Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University Hospital Regensburg, Génétique, Reproduction et Développement (GReD), Centre de Recherche en Nutrition Humaine Auvergne [CHU Clermont-Ferrand] (CRNH A), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), and Assuncao de Carvalho, Manuela
Subjects: 0301 basic medicine, Male, Physiology, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Apoptosis, Biochemistry, Androgen deprivation therapy, Prostate cancer, White Blood Cells, Mice, 0302 clinical medicine, Prostate, Animal Cells, Immune Physiology, Neoplasms, Medicine and Health Sciences, Tumor Microenvironment, Biology (General), Reproductive System Procedures, Immune Response, Liver X Receptors, Innate Immune System, Cell Death, General Neuroscience, Prostate Cancer, Prostate Diseases, 3. Good health, medicine.anatomical_structure, Oncology, Cell Processes, 030220 oncology & carcinogenesis, Androgens, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Anatomy, Cellular Types, General Agricultural and Biological Sciences, Research Article, Mice, 129 Strain, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, QH301-705.5, Urology, Immune Cells, Immunology, Prostatitis, Inflammation, Surgical and Invasive Medical Procedures, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Exocrine Glands, Signs and Symptoms, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Castration, Liver X receptor, Tumor microenvironment, Blood Cells, General Immunology and Microbiology, Macrophages, Immunity, Biology and Life Sciences, Cancers and Neoplasms, Prostatic Neoplasms, Androgen Antagonists, Cell Biology, Molecular Development, medicine.disease, Androgen, Hormones, Mice, Inbred C57BL, Genitourinary Tract Tumors, Disease Models, Animal, 030104 developmental biology, Immune System, Cancer research, Prostate Gland, Clinical Medicine, Developmental Biology
Abstract: Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders., Mice lacking the liver X nuclear receptors (LXRs), crucial integrators of lipid metabolism, were used to study the response of the prostate to androgen deprivation. This reveals that lack of androgens leads to chronic inflammation due to impaired clearance of castration-induced apoptotic cells, allowing production of pro-inflammatory cytokines and promoting prostate neoplasia.
Published: 2020
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18. Genomic classification of benign adrenocortical lesions

Author: Bertrand Dousset, Simon Faillot, Anna Vaczlavik, Jean Guibourdenche, Lionel Groussin, Mathilde Sibony, Fideline Bonnet-Serrano, Stéphanie Espiard, Amandine Septier, Mario Neou, Ludivine Drougat, Marthe Rizk-Rabin, Bruno Ragazzon, Guillaume Assié, Simon Garinet, Thomas Foulonneau, Anne Jouinot, Windy Rondof, Rossella Libé, Karine Hecale-Perlemoine, Aurélien de Reyniès, Jérôme Bertherat, and Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris.
Subjects: 0301 basic medicine, Cortisol secretion, Cancer Research, Adenoma, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, medicine, Humans, Epigenetics, Benign adrenal tumors, Exome, ComputingMilieux_MISCELLANEOUS, Genomics, Hyperplasia, medicine.disease, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030104 developmental biology, Oncology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, DNA methylation, Adrenocortical Adenoma, Cancer research
Abstract: Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.
Published: 2020
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19. Identification d’une signature moléculaire d’hypercortisolisme par analyse du methylome du sang total

Author: Martin Reincke, Guillaume Assié, Lucas Bouys, Stéphanie Allassonnière, Mario Neou, Anne Riester, Thomas Lartigue, Maria-Christina Zennaro, Jérôme Bertherat, Roberta Armignacco, Amandine Septier, Felix Beuschlein, Cassandra Gaspar, Leah T. Braun, Karine Perlemoine, Anne Jouinot, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Mathématiques Appliquées - Ecole Polytechnique (CMAP), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig Maximilian University [Munich] (LMU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Universitätsspital Zürich (USZ), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 678304,H2020 ERC,ERC-2015-STG,LEASP(2016), European Project: 666992,H2020 Pilier Societal Challenges,H2020-PHC-2015-two-stage,EuroPOND(2016), European Project: 826421,TVB-Cloud (2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Lartigue, Thomas, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Learning spatiotemporal patterns in longitudinal image data sets of the aging brain - LEASP - - H2020 ERC2016-09-01 - 2021-08-31 - 678304 - VALID, Data-driven models for Progression Of Neurological Disease - EuroPOND - - H2020 Pilier Societal Challenges2016-01-01 - 2019-12-31 - 666992 - VALID, VirtualBrainCloud - TVB-Cloud - 2018-12-01 - 2022-11-30 - 826421 - VALID, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], Endocrinology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], General Medicine
Abstract: Le diagnostic d’hypercortisolisme repose sur les dosages hormonaux. Or ces dosages ne refletent pas le risque individuel pour chaque complication de l’hypercortisolisme, car la susceptibilite interindividuelle varie, notamment dans les formes infra-cliniques. Objectif Identifier des biomarqueurs refletant l’impregnation individuelle en glucocorticoides a partir du methylome du sang total. Methodes Un total de 47 patients avec Cushing, separes en deux cohortes : entrainement (cas francs, n = 24) et validation (cas limites, n = 23). Pour chacun, prelevement d’une paire d’echantillons sanguins : avant et > 3 mois apres correction de l’hypercortisolisme. Generation du methylome du sang total par puce Illumina (850 K sondes). Resultats Dans la cohorte d’entrainement, la methylation de 28 % du genome varie selon le statut cortisolique. Le taux de polynucleaires neutrophiles infere a partir du methylome est fortement correle a la NFS (r = 0,81). Cette variation de NFS est, comme attendue, associee au statut cortisolique. Pour predire le statut Cushing/non Cushing a partir du methylome, une approche de regression penalisee basee uniquement sur la part non predite par la NFS identifie une combinaison de quelques endroits du genome (accuracies de 1 et 0,8 sur cohortes d’entrainement et de validation respectivement), qui ameliore la prediction sur la cohorte de validation par rapport a la NFS seule (accuracy = 0,65). Conclusion La methylation du genome est un biomarqueur de l’hypercortisolisme. Plusieurs questions sont en suspens, telles que la possibilite d’optimiser des techniques simples de mesures ciblees de methylation, la performance de ce biomarqueur dans les hypercortisolismes a minima, et les liens du profil de methylation avec les complications de l’hypercortisolisme.
Published: 2020
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20. Clinical implications of Pan-genomic classification of pituitary neuroendocrine tumours

Author: Roberta Armignacco, Mario Neou, Jérôme Bertherat, Michèle Bernier, Bertrand Baussart, Chiara Villa, Amandine Septier, Jouinot Anne, Karine Perlemoine, Marie-Laure Raffin-Sanson, Stephan Gaillard, and Assié Guillaume
Published: 2020
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21. Hypercortisolism-related molecular signature: Results from whole blood methylome analysis

Author: Maria-Christina Zennaro, Amandine Septier, Mario Neou, Roberta Armignacco, Anne Jouinot, Martin Reincke, Cassandra Gaspar, Lucas Bouys, Karine Perlemoine, Felix Beuschlein, Guillaume Assié, Jérôme Bertherat, Anna Riester, and Leah T. Braun
Subjects: DNA methylation, Computational biology, Biology, Signature (logic), Whole blood
Published: 2020
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22. Identification of transcriptome profiles in paraffin samples using 3’ RNA-sequencing for the prognostic assessment of adrenocortical carcinoma

Author: Jérôme Bertherat, Roberta Armignacco, Lionel Groussin, Sébastien Gaujoux, Brigitte Izac, Franck Letourneur, Amandine Septier, Guillaume Assié, Mathilde Sibony, Karen Leroy, Karine Perlemoine, Bertrand Dousset, Anne Jouinot, Rossella Libé, Lindsay Jeanpierre, Bruno Ragazzon, and Murat Daniel De
Subjects: medicine, Adrenocortical carcinoma, RNA, Transcriptome Profiles, Identification (biology), Computational biology, Biology, medicine.disease
Published: 2020
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23. Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma

Author: Mario Neou, Bertrand Dousset, Cristina L Ronchi, Sébastien Gaujoux, Juliane Lippert, Anne Jouinot, Bruno de La Villéon, Rossella Libé, Jérôme Bertherat, Lionel Groussin, Karine Perlemoine, Amandine Septier, Silke Appenzeller, Mathilde Sibony, Guillaume Assié, and Martin Fassnacht
Subjects: 0301 basic medicine, Endocrinology, Diabetes and Metabolism, intratumor heterogeneity, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Germline mutation, CDKN2A, Internal Medicine, adrenocortical carcinoma, chromosome alterations, Medicine, Adrenocortical carcinoma, lcsh:RC648-665, business.industry, Research, Chromosome, Methylation, medicine.disease, Primary tumor, 030104 developmental biology, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, somatic mutations, methylation, business
Abstract: Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level. Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12). Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were ‘Noisy’ (numerous and anarchic alterations) in 8/14 and ‘Chromosomal’ (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%). Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.
Published: 2020

24. Pangenomic classification of pituitary neuroendocrine tumors

Author: Anne Jouinot, Karine Perlemoine, Stephan Gaillard, Franck Letourneur, Denis Laloë, Cassandra Gaspar, Marie-Laure Raffin-Sanson, Bertrand Baussart, Anne Boulin, Marc Diedisheim, Xavier Bertagna, Michèle Bernier, Victoria Verjus, Amandine Septier, Mario Neou, Ségolène Diry, Chiara Villa, Roberta Armignacco, Jean-François Emile, Brigitte Izac, Florence Jaffrezic, Guillaume Assié, Jérôme Bertherat, CCSD, Accord Elsevier, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Paris Cité (UPCité), Department of Pathological Cytology and Anatomy, Hôpital Foch [Suresnes], Department of Endocrinology B 35, Centre Hospitalier Universitaire Sart Tilman, Hôpital Ambroise Paré, Department of Endocrinology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), U 1016/ UMR 8104 Institut Cochin, Plate-Forme Séquençage et Génomique (Genom'IC), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Ambroise Paré [AP-HP], Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris Saclay (COMUE), U 1016/ UMR 8104 Institut Cochin, Université de Paris (UP), Department of Diabetology, Hôpital Cochin, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Department of Diagnostic and Interventional Neuroradiology, Department of Pathology, Ambroise Paré, U 1016/ UMR 8104 Institut Cochin, Department of Endocrinology, Center for Rare Adrenal Diseases, Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Neurosurgery, Hospital Germans Trias I Pujol, Université de Paris, Assistance Publique - Hôpitaux de Paris (AP-HP), UMS PASS, Plateforme Post-génomique de la Pitié-Salpêtrière, Sorbonne Université, and Institut National de la Recherche Agronomique (INRA)-AgroParisTech
Subjects: Male, 0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Neuroendocrine tumors, methylome, pituitary neuroendocrine tumors (PitNETs), Epigenesis, Genetic, Transcriptome, genomic, Epigenome, 0302 clinical medicine, Chromosome instability, 050207 economics, Exome, Aged, 80 and over, 050208 finance, 05 social sciences, Transdifferentiation, miRNome, Middle Aged, Prognosis, [SDV] Life Sciences [q-bio], Neuroendocrine Tumors, Oncology, Pituitary Gland, 030220 oncology & carcinogenesis, DNA methylation, outcome, Female, Ubiquitin Thiolesterase, hormones, hormone substitutes, and hormone antagonists, Adult, endocrine system, Lineage (genetic), Adolescent, Somatotropic cell, Biology, Young Adult, 03 medical and health sciences, Endopeptidases, 0502 economics and business, medicine, chromosome alterations, Humans, Cell Lineage, Neoplasm Invasiveness, Pituitary Neoplasms, Epigenetics, Aged, Chromosome Aberrations, Endosomal Sorting Complexes Required for Transport, business.industry, DNA Methylation, medicine.disease, Chromosome Alterations, 030104 developmental biology, Mutation, Cancer research, Corticotropic cell, business, transcriptome, exome
Abstract: Summary Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.
Published: 2020
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25. Identification of a molecular signature of hypercortisolism by whole blood methylome analysis

Author: Guillaume Assié, Roberta Armignacco, Mario Neou, Martin Reincke, Jérôme Bertherat, Cassandra Gaspar, Maria-Christina Zennaro, Amandine Septier, Anne Jouinot, Karine Perlemoine, and Felix Beuschlein
Subjects: DNA methylation, Identification (biology), Computational biology, Biology, Signature (logic), Whole blood
Published: 2019
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26. Pan-genomic classification of pituitary adenomas

Author: Karine Perlemoine, Bertrand Baussart, Chiara Villa, Guillaume Assié, Stephan Gaillard, Michèle Bernier, Anne Jouinot, Marie-Laure Raffin-Sanson, Roberta Armignacco, Jérôme Bertherat, Amandine Septier, and Mario Neou
Published: 2019
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27. MON-LB081 Pituitary Adenomas: A Pan-genomic Classification

Author: Guillaume Assié, Jérôme Bertherat, Bertrand Baussart, Amandine Septier, Mario Neou, Karine Perlemoine, Chiara Villa, Stephan Gaillard, Marie-Laure Raffin-Sanson, Anne Jouinot, Roberta Armignacco, and Michèle Bernier
Subjects: endocrine system, Neuroendocrinology and Pituitary, Text mining, business.industry, Endocrinology, Diabetes and Metabolism, Computational biology, Pituitary Tumors and GHRH, GH, and IGF Biology and Signaling, Biology, business
Abstract: Pituitary adenomas are now called neuroendocrine tumors (PitNETs). Histological type, secretion, invasion and growth speed vary. A World Health Organization (WHO) histo-prognostic classification was released in 2017. Pituitary tumorigenesis is largely unexplained. Rare germline mutations (MENIN, AIP), and common somatic mutations in GNAS and USP8 are reported. Recently, genomic analyses have been reported. Yet, driver genes and pathways remain to be fully identified, as well as a comprehensive view of omics in the different subtypes of PitNETs Aim: To provide a genomic unbiased classification of PitNETs Methods: A clinical, histological and genomic characterization of 134 PitNETs of all subtypes was performed, combining exome, RNA and miRNA sequencing, SNP array and methylation array. Unsupervised classifications were generated. Results: Median somatic mutation rate was 95, mainly C>T belonging to “signature 1” signature. No difference was observed between histo-types. Only GNAS and USP8 presented >5% mutations. Three chromosome alteration profiles were identified: extended losses, “quiet” profiles, and extended gains. Gonadotroph and silent corticotroph were mainly “quiet”. Chromosomal alterations were not related to aggressiveness. MiRnome and methylome were associated with PitNETs histological type and secretion (chi2 p
Published: 2019
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28. Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex

Author: T. Dumontet, Jean-Christophe Pointud, Anne-Marie Lefrançois-Martinez, Isabelle Sahut-Barnola, Cyril Djari, Igor Tauveron, Amandine Septier, Gwenneg Kerdivel, Christelle Damon-Soubeyrand, Coralie Drelon, Damien Richard, Annabel Berthon, Marie-Ange Calméjane, Pierre Val, Houda Tabbal, M. Batisse-Lignier, Antoine Martinez, Mickael Mathieu, Valentina Boeva, Stéphanie Rodriguez, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), CHU Gabriel Montpied (CHU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, endocrine system, Cellular differentiation, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, 03 medical and health sciences, 0302 clinical medicine, Zona fasciculata, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Adrenal insufficiency, Animals, Enhancer of Zeste Homolog 2 Protein, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Cyclic Nucleotide Phosphodiesterases, Type 7, Multidisciplinary, Adrenal cortex, Chemistry, EZH2, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cyclic Nucleotide Phosphodiesterases, Type 1, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 3, Cell biology, Mice, Inbred C57BL, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, medicine.anatomical_structure, PNAS Plus, Zona glomerulosa, 030220 oncology & carcinogenesis, Histone methyltransferase, Pka signaling, Adrenal Cortex, Cyclic AMP-Dependent Protein Kinase RIbeta Subunit, Female, Steroids, Zona Glomerulosa, Zona Fasciculata, Homeostasis, Signal Transduction
Abstract: International audience; Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endo-crine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phospho-diesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state. adrenal | differentiation | progenitors | PKA signaling | EZH2
Published: 2018
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29. Classification génomique intégrée des tumeurs neuroendocrines hypophysaires : implications cliniques

Author: Chiara Villa, Michèle Bernier, Anne Jouinot, Bertrand Baussart, Amandine Septier, Mario Neou, S. Gaillard, Karine Perlemoine, Guillaume Assié, Marie-Laure Raffin-Sanson, Roberta Armignacco, and Jérôme Bertherat
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Recemment, nous avons genere la premiere classification genomique integree des tumeurs neuroendocrines hypophysaires (PitNETs). Objectif Explorer les implications cliniques de cette nouvelle classification. Methodes Leanalyse des donnees cliniques, hormonales et pathologiques de la serie de 134 tumeurs caracterisees par la genomique. Resultats Sur la base de la classification moleculaire, des seuils d’immunopositivite ont pu etre etablis pour la PRL, la GH et l’ACTH. L’agressivite n’est pas un determinant majeur de la classification genomique. Notamment le nombre d’alterations chromosomiques n’est pas lie a l’agressivite, mais au type de secretion. Pour les corticotropes, les mutes USP8 sont moins agressifs. Le temozolomide, recommande pour les tumeurs agressives, est degrade par le MGMT. L’association entre MGMT et la reponse au temozolomide a ete evaluee chez trois patients. Le niveau d’expression etait lie a la reponse. Aucune correlation n’a ete trouvee entre l’expression de MGMT et la methylation de son promoteur (r median 0,55 ; de −0,27 a 0,76). Les recepteurs de la somatostatine ont une expression variable entre les groupes moleculaires (Kruskal–Wallis, p Discussion Ces donnees definissent des caracteristiques moleculaires associees a l’agressivite et potentiellement a la reponse aux traitements, et ouvrent la voie a des etudes specifiques de confirmation.
Published: 2020
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30. Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer

Author: Anke Loregger, Luigi Iuliano, Julie Dufour, Allan Fouache, Pierre Val, Anthony Alioui, Martina Moeton, Vincenzo Russo, Amandine Septier, Silvère Baron, Chiara Zerbinati, Valerio Leoni, Noam Zelcer, Jean-Marc A. Lobaccaro, and David H. Volle
Subjects: 0301 basic medicine, TheoryofComputation_COMPUTATIONBYABSTRACTDEVICES, Science, General Physics and Astronomy, Context (language use), General Biochemistry, Genetics and Molecular Biology, Metastasis, 03 medical and health sciences, Prostate cancer, Prostate, Medicine, PTEN, Tensin, lcsh:Science, Liver X receptor, Multidisciplinary, biology, business.industry, Cancer, General Chemistry, medicine.disease, TheoryofComputation_MATHEMATICALLOGICANDFORMALLANGUAGES, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Cancer research, lcsh:Q, business
Abstract: Advanced prostate cancer (PCa) is a clinical challenge as no curative therapeutic is available. In this context, a better understanding of metastasis and resistance mechanisms in PCa is an important issue. As phosphatase and tensin homolog (PTEN) loss is the most common genetic lesion in such cancer, we investigate human data sets for mechanisms that can constrain cancer evolution in this setting. Here we report a liver X receptor (LXR) signature, which tightly correlates with PTEN loss, in PCa. Accordingly, the LXR pathway is deregulated in prostate carcinomas in Pten-null mice. Genetic ablation of LXRs in Pten-null mice, exacerbates PCa invasiveness and metastatic dissemination, which involves mesenchymal transition and accumulation of matrix metalloproteinases. Mechanistically, PTEN deletion governed LXR transcriptional activity through deregulation of cholesterol de novo synthesis, resulting in accumulation of endogenous LXR ligands. Our study therefore reveals a functional circuit linking PTEN and LXR, and highlights LXRs as metabolic gatekeepers that are able to constrain PCa progression. Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors.
Published: 2018
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31. Adrenocortical development: Lessons from mouse models

Author: T. Dumontet, Pierre Val, Nathanaëlle Montanier, Antoine Martinez, Isabelle Sahut-Barnola, Anne Marie Lefrançois-Martinez, David T. Breault, Ingrid Plotton, Amandine Septier, Jean Christophe Pointud, Véronique Ducros, Mohamad Zubair, Florence Roucher-Boulez, Ken Ichirou Morohashi, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’endocrinologie diabétologie et maladies métaboliques, CHU Clermont-Ferrand, Hospices Civils de Lyon (HCL), CHU Lyon, Département de biologie intégrée, CHU Grenoble-Hôpital Michallon, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: Sexual Maturation, MESH: Mice, Knockout, Cushing syndrome, Mice, 0302 clinical medicine, Endocrinology, Adrenal Glands, PKA, MESH: Animals, Sexual Maturation, MESH: Adrenal Glands, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Adrenal cortex, Wnt signaling pathway, Cell Differentiation, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.anatomical_structure, Zone réticulée, MESH: Models, Animal, Models, Animal, Zona reticularis, Female, MESH: Cell Differentiation, medicine.medical_specialty, Modèle animal, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Zona fasciculata, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, Involution (medicine), Animal model, MESH: Mice, Fetus, Syndrome de Cushing, Cortex surrénalien, MESH: Humans, Adrenarche, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Adrenal Cortex, MESH: Adrenal Cortex, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; The adrenocortical gland undergoes structural and functional remodelling in the fetal and postnatal periods. After birth, the fetal zone of the gland undergoes rapid involution in favor of the definitive cortex, which reaches maturity with the emergence of the zona reticularis(zR) at the adrenarche. The mechanisms underlying the adrenarche, the process leading to pre-puberty elevation of plasma androgens in higher primates, remain unknown, largely due to lack of any experimental model. By following up fetal and definitive cortex cell lines in mice, we showed that activation of protein kinase A (PKA) signaling mainly impacts the adult cortex by stimulating centripetal regeneration, with differentiation and then conversion of the zona fasciculata into a functional zR. Animals developed Cushing syndrome associated with primary hyperaldosteronism, suggesting possible coexistence of these hypersecretions in certain patients. Remarkably, all of these traits were sex-dependent: testicular androgens promoted WNT signaling antagonism on PKA, slowing cortical renewal and delaying onset of Cushing syndrome and the establishment of the zR in male mice, this being corrected by orchidectomy. In conclusion, zR derives from centripetal conversion of the zona fasciculata under cellular renewal induced by PKA signaling, determining the size of the adult cortex. Finally, we demonstrated that this PKA-dependent mobilization of cortical progenitors is sexually dimorphic and could, if confirmed in humans, account for female preponderance in adrenocortical pathologies.
Published: 2018
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32. EZH2: a master regulator of adrenal cortex homeostasis and zonation

Author: Coralie Drelon, Amandine Septier, Houda Tabbal, Antoine Martinez, Mickael Mathieu, A. Berthon, Stéphanie Rodriguez, David Sainte-Catherine, and David T. Breault
Subjects: medicine.medical_specialty, Endocrinology, medicine.anatomical_structure, Adrenal cortex, Internal medicine, EZH2, medicine, Master regulator, Biology, Neuroscience, Homeostasis
Published: 2017
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33. Méthylome du sang total : à la recherche de nouveaux marqueurs biologiques du syndrome de Cushing

Author: Roberta Armignacco, Karine Perlemoine, Jérôme Bertherat, Felix Beuschlein, Amandine Septier, Cassandra Gaspar, and Guillaume Assié
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Le diagnostic du syndrome de Cushing repose essentiellement sur les dosages hormonaux. Or parfois le diagnostic positif est difficile, des nouveaux marqueurs d’hypercortisolisme facilement mesurables pourraient l’ameliorer. Comme montrees par des etudes anterieures, des marques epigenetiques associees au stress sont mesurables dans le sang total par le profil de methylation d’ADN leucocytaire. Objectif Analyser le profil de methylation de patients avec syndrome de Cushing avant et apres correction d’hypercortisolisme pour l’identification de biomarqueurs specifiques. Materiel et methodes Huit patients avec syndrome de Cushing hypophysaire franc ont ete inclus. Chacun dispose d’une couple d’echantillons sanguins, l’un preleve avant la chirurgie hypophysaire et l’autre preleve plusieurs mois apres, pour l’extraction de l’ADN leucocytaire. Le methylome a ete genere par puce Infinium®MethylationEPIC BeadChip (Illumina, 850k sondes). Les niveaux de methylation ont ete generes avec logiciel GenomeStudio (Illumina, version 2011.1). L’analyse bioinformatique a ete realisee avec logiciel R (version 3.4.4), principalement par clustering non supervise (Hclust). Resultats Le clustering non supervise des donnees de methylome montre une repartition des 16 echantillons en 8 paires, chacune correspondant a un individu (pre/post chirurgie). Pour 7 patients sur 8 (p = 0,035), une signature d’hypermethylation est identifiee, associee specifiquement au statut d’hypercortisolisme, correspondant a des sondes reparties sur plusieurs regions du genome. Conclusions Nos resultats preliminaires montrent l’existence d’une signature epigenetique specifique de l’hypercortisolisme dans le sang, qui doit etre confirmee sur une cohorte plus large. En particulier, il faudra tester la valeur de cette signature sur d’autres etiologies d’hypercortisolisme, et sur des niveaux modestes d’hypercortisolisme.
Published: 2018
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34. EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression

Author: Pierre Val, T. Dumontet, Silvère Baron, Antoine Martinez, M. Batisse-Lignier, Jean Christophe Pointud, Mickael Mathieu, Anne Marie Lefrançois-Martinez, Bruno Ragazzon, Rork Kuick, Stéphanie Rodriguez, Annabel Berthon, Isabelle Sahut-Barnola, Houda Tabbal, Jérôme Bertherat, Coralie Drelon, Thomas J. Giordano, Amandine Septier, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche Universitaire Lorrain d'Histoire (CRULH), Université de Lorraine (UL), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: 0301 basic medicine, medicine.medical_treatment, MESH: beta Catenin, Gene Expression, MESH: Adrenal Cortex Neoplasms, MESH: Insulin-Like Growth Factor II, Mice, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Adrenocortical carcinoma, Mitotane, MESH: Animals, Wnt Signaling Pathway, beta Catenin, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, EZH2, Wnt signaling pathway, MESH: Genetic Predisposition to Disease, MESH: Wnt Signaling Pathway, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 030220 oncology & carcinogenesis, Histone methyltransferase, Disease Progression, RNA Interference, MESH: Disease Progression, Growth inhibition, Databases, Nucleic Acid, medicine.drug, MESH: Gene Expression, MESH: Cell Line, Tumor, MESH: Mice, Transgenic, MESH: RNA Interference, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Databases, Nucleic Acid, Article, 03 medical and health sciences, Insulin-Like Growth Factor II, Cell Line, Tumor, MESH: Cell Proliferation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Carcinoma, MESH: Enhancer of Zeste Homolog 2 Protein, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Genetic Predisposition to Disease, Molecular Biology, MESH: Mice, Cell Proliferation, MESH: Humans, Growth factor, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Adrenal Cortex Neoplasms, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, Cancer research
Abstract: International audience; Adrenal Cortex Carcinoma (ACC) is an aggressive tumour with poor prognosis. Common alterations in patients include constitutive WNT/β-catenin signalling and overexpression of the growth factor IGF2. However, the combination of both alterations in transgenic mice is not sufficient to trigger malignant tumour progression, suggesting that other alterations are required to allow development of carcinomas. Here, we have conducted a study of publicly available gene expression data from three cohorts of ACC patients to identify relevant alterations. Our data show that the histone methyltransferase EZH2 is overexpressed in ACC in the three cohorts. This overexpression is the result of deregulated P53/RB/E2F pathway activity and is associated with increased proliferation and poorer prognosis in patients. Inhibition of EZH2 by RNA interference or pharmacological treatment with DZNep inhibits cellular growth, wound healing and clonogenic growth and induces apoptosis of H295R cells in culture. Further growth inhibition is obtained when DZNep is combined with mitotane, the gold-standard treatment for ACC. Altogether, these observations suggest that overexpression of EZH2 is associated with aggressive progression and may constitute an interesting therapeutic target in the context of ACC.
Published: 2016
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35. Génomique intégrée des lésions corticosurrénaliennes bénignes

Author: Karine Perlemoine, F. Bonnet, Lionel Groussin, L. Drougat, Anne Jouinot, Jean Guibourdenche, Mathilde Sibony, Bruno Ragazzon, Jérôme Bertherat, W. Luscap Rondof, A. De Reyniès, Guillaume Assié, Bertrand Dousset, M. Rizk Rabin, Rossella Libé, Amandine Septier, Simon Garinet, Anna Vaczlavik, S. Faillot, Stéphanie Espiard, Frédérique Tissier, and Mario Neou
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Les lesions corticosurrenaliennes benignes regroupent un large eventail de maladies avec des morphologies ainsi que des secretions de steroides distinctes. Contrairement au corticosurrenalome, aucune vision globale moleculaire des alterations moleculaires n’est disponible pour ces tumeurs. Objectifs Fournir une classification moleculaire des tumeurs corticosurrenaliennes benignes, en utilisant une serie de mesures non biaisees pan-genomiques dans une cohorte incluant tous les types de tumeurs corticosurrenaliennes benignes. Methodes L’etude effectuee rapporte l’analyse pan-genomique incluant transcriptome, miRNome, methylome, mutations et alterations chromosomiques de 146 lesions adrenocorticales benignes. Resultats Le transcriptome, le methylome, le miRNome et le statut mutationnel convergent en une seule classification avec quatre groupes principaux : (i) les tumeurs productrices de cortisol, regroupant differents types partageant une activation commune de la voie AMPc/PKA par des mecanismes distincts. Le transcriptome a permis d’identifier une signature steroidogene ; (ii) des adenomes corticosurrenaliens (ACA) sans ou avec une secretion legere de cortisol, associes a des mutations de la beta-catenine ; (iii) des hyperplasies macronodulaires primaires avec des mutations ARMC5, montrant une signature d’expression ovarienne ; (iv) des ACA produisant de l’aldosterone, en dehors d’autres tumeurs benignes. Les alterations epigenetiques et la steroidogenese semblent associees, incluant l’hypomethylation des ilots CpG dans les tumeurs sans ou avec une secretion legere de cortisol, les profils des miARN definissant des groupes moleculaires specifiques, et la regulation directe de l’expression des enzymes steroidogenes par la methylation. Conclusion Cette premiere caracterisation pan-genomique a grande echelle des lesions corticosurrenaliennes benignes represente une nouvelle ressource importante pour l’etude de la tumorigenese corticosurrenalienne et de la steroidogenese.
Published: 2018
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35 results on '"Amandine Septier"'

1. Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function

2. Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma

3. Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia.

4. RETRACTED ARTICLE: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer

5. Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer

6. Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia

7. Whole blood methylome-derived features to discriminate endocrine hypertension

8. Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma

9. Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

10. Identification of glucocorticoid-related molecular signature by whole blood methylome analysis

11. Le profil de méthylome du sang total comme biomarqueur de l’excès des glucocorticoïdes

12. EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness

13. PDE11A4 (Phosphodiesterase 11 A4) is a modulator of the primary bilateral macronodular adrenal hyperplasia (PBMAH) phenotype: genotype/phenotype analysis of a cohort of 354 patients analysed by next-generation sequencing (NGS)

14. Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors

15. PKA drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

16. Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player

17. Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia

18. Genomic classification of benign adrenocortical lesions

19. Identification d’une signature moléculaire d’hypercortisolisme par analyse du methylome du sang total

20. Clinical implications of Pan-genomic classification of pituitary neuroendocrine tumours

21. Hypercortisolism-related molecular signature: Results from whole blood methylome analysis

22. Identification of transcriptome profiles in paraffin samples using 3’ RNA-sequencing for the prognostic assessment of adrenocortical carcinoma

23. Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma

24. Pangenomic classification of pituitary neuroendocrine tumors

25. Identification of a molecular signature of hypercortisolism by whole blood methylome analysis

26. Pan-genomic classification of pituitary adenomas

27. MON-LB081 Pituitary Adenomas: A Pan-genomic Classification

28. Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex

29. Classification génomique intégrée des tumeurs neuroendocrines hypophysaires : implications cliniques

30. Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer

31. Adrenocortical development: Lessons from mouse models

32. EZH2: a master regulator of adrenal cortex homeostasis and zonation

33. Méthylome du sang total : à la recherche de nouveaux marqueurs biologiques du syndrome de Cushing

34. EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression

35. Génomique intégrée des lésions corticosurrénaliennes bénignes

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35 results on '"Amandine Septier"'

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