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1. NF-κB signaling activation and roles in thyroid cancers: implication of MAP3K14/NIK

Author: Françoise Cormier, Selma Housni, Florent Dumont, Mélodie Villard, Béatrix Cochand-Priollet, Françoise Mercier-Nomé, Karine Perlemoine, Jérôme Bertherat, and Lionel Groussin
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Among follicular-derived thyroid cancers (TC), those with aggressive behavior and resistance to current treatments display poor prognosis. NF-κB signaling pathways are involved in tumor progression of various cancers. Here, we finely characterize the NF-κB pathways and their involvement in TC. By using immunoblot and gel shift assays, we demonstrated that both classical and alternative NF-κB pathways are activated in ten TC-derived cell lines, leading to activated RelA/p50 and RelB/p50 NF-κB dimers. By analyzing the RNAseq data of the large papillary thyroid carcinoma (PTC) cohort from The Cancer Genome Atlas (TCGA) project, we identified a tumor progression-related NF-κB signature in BRAFV600E mutated-PTCs. That corroborated with the role of RelA and RelB in cell migration and invasion processes that we demonstrated specifically in BRAFV600E mutated-cell lines, together with their role in the control of expression of genes implicated in invasiveness (MMP1, PLAU, LCN2 and LGALS3). We also identified NF-κB-inducing kinase (NIK) as a novel actor of the constitutive activation of the NF-κB pathways in TC-derived cell lines. Finally, its implication in invasiveness and its overexpression in PTC samples make NIK a potential therapeutic target for advanced TC treatment.
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. ARMC5 mutation in a Portuguese family with primary bilateral macronodular adrenal hyperplasia (PBMAH)

Author: Teresa Rego, Fernando Fonseca, Stéphanie Espiard, Karine Perlemoine, Jérôme Bertherat, and Ana Agapito
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: PBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH
Published: 2017
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4. Silencing mutated β-catenin inhibits cell proliferation and stimulates apoptosis in the adrenocortical cancer cell line H295R.

Author: Sébastien Gaujoux, Constanze Hantel, Pierre Launay, Stéphane Bonnet, Karine Perlemoine, Lucile Lefèvre, Marine Guillaud-Bataille, Felix Beuschlein, Frédérique Tissier, Jérôme Bertherat, Marthe Rizk-Rabin, and Bruno Ragazzon
Subjects: Medicine, Science
Abstract: ContextAdrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm, with limited therapeutic options. Activating β-catenin somatic mutations are found in ACC and have been associated with a poor clinical outcome. In fact, activation of the Wnt/β-catenin signaling pathway seems to play a major role in ACC aggressiveness, and might, thus, represent a promising therapeutic target.ObjectiveSimilar to patient tumor specimen the H295 cell line derived from an ACC harbors a natural activating β-catenin mutation. We herein assess the in vitro and in vivo effect of β-catenin inactivation using a doxycyclin (dox) inducible shRNA plasmid in H295R adrenocortical cancer cells line (clone named shβ).ResultsFollowing dox treatment a profound reduction in β-catenin expression was detectable in shβ clones in comparison to control clones (Ctr). Accordingly, we observed a decrease in Wnt/βcatenin-dependent luciferase reporter activity as well as a decreased expression of AXIN2 representing an endogenous β-catenin target gene. Concomitantly, β-catenin silencing resulted in a decreased cell proliferation, cell cycle alterations with cell accumulation in the G1 phase and increased apoptosis in vitro. In vivo, on established tumor xenografts in athymic nude mice, 9 days of β-catenin silencing resulted in a significant reduction of CTNNB1 and AXIN2 expression. Moreover, continous β-catenin silencing, starting 3 days after tumor cell inoculation, was associated with a complete absence of tumor growth in the shβ group while tumors were present in all animals of the control group.ConclusionIn summary, these experiments provide evidences that Wnt/β-catenin pathway inhibition in ACC is a promising therapeutic target.
Published: 2013
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5. Description of 38 novel ARMC5 variants and review of the literature: the updated mutational landscape of ARMC5 in Bilateral Macronodular Adrenocortical Disease

Author: Lucas Bouys, Anna Vaczlavik, Cavalcante Isadora Pontes, Florian Violon, Anne Jouinot, Annabel Berthon, Patricia Vaduva, Stephanie Espiard, Karine Perlemoine, Peter Kamenicky, Marie-Christine Vantyghem, Antoine Tabarin, Gerald Raverot, Cristina Ronchi, Ulrich Dischinger, Martin Reincke, Barisson Villares Fragoso Maria Candida, Constantine Stratakis, Marie-Odile North, Eric Pasmant, Bruno Ragazzon, and Jerome Bertherat
Subjects: General Medicine
Published: 2023
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6. Study of somatic molecular heterogeneity in bilateral macronodular adrenocortical disease (BMAD) by NGS panel in a cohort of 26 patients

Author: Florian Violon, Lucas Bouys, Giannone Gaetan, Patricia Vaduva, Karine Perlemoine, Annabel Berthon, Bruno Ragazzon, Mathilde Sibony, and Jerome Bertherat
Subjects: General Medicine
Published: 2023
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7. Tumor microenvironment of adrenocortical carcinoma dissected by single-cell RNA-sequencing

Author: Anne Jouinot, Yoann Martin, Thomas Foulonneau, Yanis Bendjelal, Philip Calvet, Florian Violon, Mathilde Sibony, De Murat Daniel, Roberta Armignacco, Karine Perlemoine, Franck Letourneur, Brigitte Izac, Muriel Andrieu, Annabel Berthon, Bruno Ragazzon, Lionel Groussin, Rossella Libe, Jerome Bertherat, and Guillaume Assie
Subjects: General Medicine
Published: 2023
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8. Supplementary Video 1 from Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors

Author: Constantine A. Stratakis, Jérôme Bertherat, Lionel Groussin, Yianna Patronas, Maria Nesterova, Frank Weinberg, Audrey Robinson-White, Michael Muchow, Karine Perlemoine, Glawdys Fumey, Miriam L. Shiferaw, Sotiris Stergiopoulos, Anelia Horvath, Manos Mavrakis, Laure Cazabat, Ioannis Bossis, and Elise Meoli
Abstract: Supplementary Video 1 from Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors
Published: 2023
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9. Supplementary Table 1 from Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells

Author: Jérôme Bertherat, Antoine Martinez, Karine Perlemoine, Hélène Fierrard, Lionel Groussin, Guillaume Assie, Marthe Rizk-Rabin, Laure Cazabat, and Bruno Ragazzon
Abstract: Supplementary Table 1 from Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells
Published: 2023
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10. sSupplementary Video 3 from Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors

Author: Constantine A. Stratakis, Jérôme Bertherat, Lionel Groussin, Yianna Patronas, Maria Nesterova, Frank Weinberg, Audrey Robinson-White, Michael Muchow, Karine Perlemoine, Glawdys Fumey, Miriam L. Shiferaw, Sotiris Stergiopoulos, Anelia Horvath, Manos Mavrakis, Laure Cazabat, Ioannis Bossis, and Elise Meoli
Abstract: sSupplementary Video 3 from Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors
Published: 2023
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11. Data from Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells

Author: Jérôme Bertherat, Antoine Martinez, Karine Perlemoine, Hélène Fierrard, Lionel Groussin, Guillaume Assie, Marthe Rizk-Rabin, Laure Cazabat, and Bruno Ragazzon
Abstract: The cyclic AMP signaling pathway can be altered at multiple levels in endocrine tumors. Its central component is the protein kinase A (PKA). Carney complex (CNC) is a hereditary multiple neoplasia syndrome resulting from inactivating mutations of the gene encoding the PKA type I α regulatory subunit (PRKAR1A). Primary pigmented nodular adrenocortical disease is the most frequent endocrine tumor of CNC. Transforming growth factor β (TGFβ) regulates adrenal cortex physiology and signals through SMAD2/3. We used an interference approach to test the effects of PRKAR1A inactivation on PKA and TGFβ pathways and on apoptosis in adrenocortical cells. PRKAR1A silencing stimulates PKA activity and increases transcriptional activity of a PKA reporter construct and expression of the endogenous PKA target, NR4A2, under basal conditions or after forskolin stimulation. PRKAR1A inactivation also decreased SMAD3 mRNA and protein levels via PKA, altering the cellular response to TGFβ. SMAD3 expression was also inhibited by adrenocorticorticotropic hormone in the mouse adrenal gland and by forskolin in H295R cells. TGFβ stimulates apoptosis in H295R cells, and this effect was counteracted by PRKAR1A inactivation. PRKAR1A silencing decreased the percentage of apoptotic cells and the cleavage of apoptosis mediators [caspase-3, poly(ADP-ribose) polymerase, and lamin A/C]. Inactivating mutations of PRKAR1A observed in adrenocortical tumors alter SMAD3, leading to resistance to TGFβ-induced apoptosis. This cross-talk between the PKA and the TGFβ signaling pathways reveals a new mechanism of endocrine tumorigenesis. [Cancer Res 2009;69(18):7278–84]
Published: 2023
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12. Supplementary Video 2 from Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors

Author: Constantine A. Stratakis, Jérôme Bertherat, Lionel Groussin, Yianna Patronas, Maria Nesterova, Frank Weinberg, Audrey Robinson-White, Michael Muchow, Karine Perlemoine, Glawdys Fumey, Miriam L. Shiferaw, Sotiris Stergiopoulos, Anelia Horvath, Manos Mavrakis, Laure Cazabat, Ioannis Bossis, and Elise Meoli
Abstract: Supplementary Video 2 from Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors
Published: 2023
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13. Supplementary Table 2 from Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells

Author: Jérôme Bertherat, Antoine Martinez, Karine Perlemoine, Hélène Fierrard, Lionel Groussin, Guillaume Assie, Marthe Rizk-Rabin, Laure Cazabat, and Bruno Ragazzon
Abstract: Supplementary Table 2 from Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells
Published: 2023
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14. Impact of Morphology in the Genotype and Phenotype Correlation of Bilateral Macronodular Adrenocortical Disease (BMAD): A Series of Clinicopathologically Well-Characterized 35 Cases

Author: Florian Violon, Lucas Bouys, Annabel Berthon, Bruno Ragazzon, Maxime Barat, Karine Perlemoine, Laurence Guignat, Benoit Terris, Jérôme Bertherat, and Mathilde Sibony
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine, Pathology and Forensic Medicine
Published: 2023
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15. KDM1A inactivation causes hereditary food-dependent Cushing syndrome

Author: Lucas Bouys, Guillaume Assié, Anna Vaczlavik, Florian Violon, Constantine A. Stratakis, Eric Letouzé, Maria Candida Barisson Villares Fragoso, Patricia Vaduva, Jérôme Bertherat, Marie-Odile North, Mathilde Sibony, Stéphanie Espiard, Rossella Libé, Magalie Haissaguerre, Roberta Armignacco, Bertrand Dousset, Laurence Guignat, Karine Perlemoine, Lionel Groussin, Anne Jouinot, Annabel Berthon, Christopher Ribes, Bruno Ragazzon, Martin Reincke, Fidéline Bonnet, Gaetan Giannone, Eric Pasmant, Igor Tauveron, Philippe Emy, Isadora Pontes Cavalcante, Maxime Barat, 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), 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), 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), CHU Pontchaillou [Rennes], CHU Lille, Centre Hospitalier Régional d'Orléans (CHRO), Université de Bordeaux (UB), CHU Bordeaux [Bordeaux], CHU Clermont-Ferrand, Universidade de São Paulo = University of São Paulo (USP), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, ANR-18-CE14-0008,STEROMICS,Steroïdogénomique de l'hypersécrétion des stéroïdes surrénaliens(2018), Admin, Oskar, and APPEL À PROJETS GÉNÉRIQUE 2018 - Steroïdogénomique de l'hypersécrétion des stéroïdes surrénaliens - - STEROMICS2018 - ANR-18-CE14-0008 - AAPG2018 - VALID
Subjects: medicine.medical_treatment, Adrenocortical tumors, ARMC5, Germline, Cushing syndrome, medicine, Humans, Allele, Cushing Syndrome, GIPR, Genetics (clinical), Exome sequencing, Armadillo Domain Proteins, Histone Demethylases, Hyperplasia, business.industry, Adrenalectomy, medicine.disease, Phenotype, KDM1A, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Macronodular Adrenal Hyperplasia, DNA methylation, Cancer research, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Ectopic expression, business
Abstract: International audience; PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10(-12) and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.
Published: 2022
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16. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients

Author: Lucas Bouys, Anna Vaczlavik, Anne Jouinot, Patricia Vaduva, Stéphanie Espiard, Guillaume Assié, Rossella Libé, Karine Perlemoine, Bruno Ragazzon, Laurence Guignat, Lionel Groussin, Léopoldine Bricaire, Isadora Pontes Cavalcante, Fidéline Bonnet-Serrano, Hervé Lefebvre, Marie-Laure Raffin-Sanson, Nicolas Chevalier, Philippe Touraine, Christel Jublanc, Camille Vatier, Gérald Raverot, Magalie Haissaguerre, Luigi Maione, Matthias Kroiss, Martin Fassnacht, Sophie Christin-Maitre, Eric Pasmant, Françoise Borson-Chazot, Antoine Tabarin, Marie-Christine Vantyghem, Martin Reincke, Peter Kamenicky, Marie-Odile North, Jérôme Bertherat, 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), 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), CHU Pontchaillou [Rennes], CHU Lille, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Rouen, Normandie Université (NU), Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Hôpital Haut-Lévêque - CHU de Bordeaux (Centre médico chirurgical Magellan), Physiologie et physiopathologie endocriniennes (PHYSENDO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), University Hospital of Würzburg, Klinikum der Universität [München], CHU Saint-Antoine [AP-HP], L B is recipient of research fellowships from the Cancer Research for Personalized Medicine (CARPEM) and the Fondation ARC pour la Recherche contre le Cancer, J B laboratory is supported by the Agence Nationale pour la Recherche grant ANR-18-CE14-0008-01 and the Fondation pour la Recherche Médicale (EQU201903007854). P T, C J, M F, S C M, F B C, M R, P C and J B clinical departments are part the European Reference Network on Rare Endocrine Conditions (Endo-ERN) – Project ID No 739572, and ANR-18-CE14-0008,STEROMICS,Steroïdogénomique de l'hypersécrétion des stéroïdes surrénaliens(2018)
Subjects: Armadillo Domain Proteins, Hyperplasia, Hydrocortisone, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], 71 ARMC5, General Medicine, genetic screening, PBMAH, Endocrinology, Primary Bilateral Macronodular Adrenal Hyperplasia, adrenal tumors, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Adrenal Glands, Humans, Cushing syndrome, tumor suppressor gene, Retrospective Studies
Abstract: Objective Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants. Methods We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively. Results 52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant. Conclusion We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.
Published: 2023
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17. Tumor suppressor gene ARMC5 controls adrenal redox state through NRF1 turnover

Author: Isadora P Cavalcante, Marthe Rizk-Rabin, Christopher Ribes, Karine Perlemoine, Constanze Hantel, Annabel Berthon, Jerome Bertherat, Bruno Ragazzon, and University of Zurich
Subjects: Armadillo Domain Proteins, Cancer Research, Nuclear Respiratory Factor 1, Superoxide Dismutase, Endocrinology, Diabetes and Metabolism, Tumor Suppressor Proteins, 10265 Clinic for Endocrinology and Diabetology, 610 Medicine & health, Peroxiredoxins, Endocrinology, Oncology, Adrenal Glands, Humans, Genes, Tumor Suppressor, Reactive Oxygen Species, Oxidation-Reduction
Abstract: ARMC5 is a tumor suppressor gene frequently mutated in primary bilateral macronodular adrenal hyperplasia (PBMAH), an adrenal cause of Cushing’s syndrome. The function of ARMC5 is poorly understood, aside the fact that it regulates cell viability and adrenal steroidogenesis by mechanisms still unknown. Tumor suppressor genes play an important role in modifying intracellular redox response, which in turn regulates diverse cell signaling pathways. In this study we demonstrated that ARMC5 inactivation in adrenocortical cell increased expression of actors scavenging ROS, such as superoxide dismutases (SOD) and peroxiredoxins (PRDX) by increasing the transcriptional regulator NRF1. Moreover, ARMC5 is involved in the NRF1 ubiquitination and in its half-life. Finally, ARMC5 inactivation alters adrenocortical steroidogenesis through activation of p38 pathway and decreases cell sensitivity to ferroptosis participating to increase cell viability. Altogether, this study uncovers a function of ARMC5 as a regulator of the redox homeostasis in adrenocortical cells, controlling steroidogenesis and cell survival.
Published: 2022

18. OR04-3 Genetic Alterations of ARMC5 and KDM1A Are Associated With Different Expression Profiles of Illegitimate Receptors in Primary Bilateral Macronodular Adrenal Hyperplasia

Author: Roberta Armignacco, Guillaume Assié, Maxime Barat, Jérôme Bertherat, Annabel Berthon, Fidéline Bonnet-Serrano, Isadora P Cavalcante, Bertrand Dousset, Gaëtan Giannone, Lionel Groussin, Laurence Guignat, Anne Jouinot, Rossella Libé, Marie-Odile North, Eric Pasmant, Karine Perlemoine, Bruno Ragazzon, Christopher Ribes, Mathilde Sibony, Anna Vaczlavik, Patricia Vaduva, Florian Violon, and Lucas Bouys
Subjects: Endocrinology, Diabetes and Metabolism
Abstract: Introduction Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a heterogeneous disease characterized by bilateral adrenal macronodules responsible for adrenal Cushing. To date, two genetic causes of PBMAH are known: germline inactivating variants of the tumor suppressor genes ARMC5 identified in 2013 (Assié, N Eng J Med 2013), responsible for 20 to 25% of index cases, and KDM1A, identified recently (Vaczlavik, GIM 2021; Chasseloup, Lancet D&E 2021), responsible for the rare presentation associated with food-dependent Cushing's syndrome (FDCS) due to aberrant expression of the GIP receptor (GIPR) in adrenocortical cells. Multiple other illegitimate receptors are known to be responsible for abnormal cortisol response to various physiological stimuli in PBMAH. A recent multiomic analysis, identified three distinct molecular PBMAH groups: G1 with ARMC5-mutated tumors, G2 with KDM1A-mutated tumors from FDCS patients, and G3 with no identified genetic cause at present. We aimed to identify specific expression profiles of illegitimate receptors in the three groups. Methods Based on the transcriptome data obtained by RNA sequencing (Illumina) of the tumors from 31 patients (G1/ARMC5, 16 patients; G2/KDM1A, 6 patients; G3, 9 patients), expression of the following genes, encoding potential illegitimate receptors, were compared: ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3, AVPR1A, AVPR1B, AVPR2, GCGR, GIPR, HTR4, HTR7, LHCGR. Calculations were performed using R statistical software. The Bioconductor limma package was used to analyze mRNA differential expression. Results G1/ARMC5 tumors showed a relative overexpression of the vasopressin receptors AVPR1A and AVPR1B compared to the two other groups (fold-change [FC] =7.39, p Conclusion This study reveals specific expression profiles of illegitimate receptors related to the three molecular groups. ARMC5 tumors are associated with the overexpression of two vasopressin receptors, while, besides GIPR, KDM1A inactivation seems to drive the overexpression of the LH/hCG receptor, as previously suggested in patients with FDCS (Bertherat, JCE&M 2005), potentially responsible for Cushing's syndrome associated with pregnancy and menopause. These molecular patterns need to be corroborated by clinical data with a systematic testing of the aberrant cortisol responses. Additionally, further studies would be needed to investigate the clinical relevance and significance of moderate fold-changes in gene expression (e.g. Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.
Published: 2022
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19. Whole blood transcriptomic profile of Cushing's syndrome

Author: Roberta Armignacco, De Murat Daniel, Anne Jouinot, Lucas Bouys, Karine Perlemoine, Franck Letourneur, Lucie Adoux, Maria-Christina Zennaro, Jerome Bertherat, and Guillaume Assie
Published: 2022
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20. Integrated genomics reveals the molecular classification of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH), correlating with specific profiles of illegitimate receptors expression and identifies KDM1A as the genetic cause of food-dependent Cushing syndrome

Author: Lucas Bouys, Florian Violon, Anna Vaczlavik, Giannone Gaetan, Anne Jouinot, Roberta Armignacco, Isadora Pontes Cavalcante, Annabel Berthon, Eric Letouze, Patricia Vaduva, Maxime Barat, Bonnet Fideline, Karine Perlemoine, Christopher Ribes, Mathilde Sibony, Marie-Odile North, Stephanie Espiard, Magalie Haissaguerre, Igor TAUVERON, Laurence Guignat, Lionel Groussin, Bertrand Dousset, Martin Reincke, Villares Fragoso Maria Candida Barisson, Constantine A Stratakis, Eric Pasmant, Rossella Libe, Guillaume Assie, Bruno Ragazzon, and Jerome Bertherat
Published: 2022
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21. Cullin 3 targets the tumor suppressor gene ARMC5 for ubiquitination and degradation

Author: Anna Vaczlavik, Eric Clauser, Isadora Pontes Cavalcante, Maria Candida Barisson Villares Fragoso, Jérôme Bertherat, Ludivine Drougat, Marthe Rizk-Rabin, Claudimara Ferini Pacicco Lotfi, Christopher Ribes, Bruno Ragazzon, Karine Perlemoine, 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, Cancer Research, Cyclin E, Tumor suppressor gene, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Mutant, Transfection, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Ubiquitin, Humans, ComputingMilieux_MISCELLANEOUS, Armadillo Domain Proteins, biology, Ubiquitination, Cell cycle, REGULAÇÃO NEOPLÁSICA DA EXPRESSÃO GÊNICA, Cullin Proteins, Cell biology, 030104 developmental biology, Oncology, Proteasome, 030220 oncology & carcinogenesis, Armadillo repeats, biology.protein, Cullin
Abstract: ARMC5 (Armadillo repeat containing 5 gene) was identified as a new tumor suppressor gene responsible for hereditary adrenocortical tumors and meningiomas. ARMC5 is ubiquitously expressed and encodes a protein which contains a N-terminal Armadillo repeat domain and a C-terminal BTB (Bric-a-Brac, Tramtrack and Broad-complex) domain, both docking platforms for numerous proteins. At present, expression regulation and mechanisms of action of ARMC5 are almost unknown. In this study, we showed that ARMC5 interacts with CUL3 requiring its BTB domain. This interaction leads to ARMC5 ubiquitination and further degradation by the proteasome. ARMC5 alters cell cycle (G1/S phases and cyclin E accumulation) and this effect is blocked by CUL3. Moreover, missense mutants in the BTB domain of ARMC5, identified in patients with multiple adrenocortical tumors, are neither able to interact and be degraded by CUL3/proteasome nor alter cell cycle. These data show a new mechanism of regulation of the ARMC5 protein and open new perspectives in the understanding of its tumor suppressor activity.
Published: 2020
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22. 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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23. 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

24. 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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25. 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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26. ARMC5 modifies cell redox state to regulate steroidogenesis and lipid metabolism in the adrenal cortex

Author: P.C. Isadora, C. Ribes, Jérôme Bertherat, Karine Perlemoine, Marthe Rizk-Rabin, and Bruno Ragazzon
Subjects: Endocrinology, medicine.anatomical_structure, Chemistry, Adrenal cortex, Endocrinology, Diabetes and Metabolism, Cell, medicine, Lipid metabolism, General Medicine, Redox, Cell biology
Published: 2021
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27. LSD1/KDM1A Inactivation Causes Hereditary Food-Dependent Cushing’s Syndrome

Author: Maxime Barat, Bruno Ragazzon, Bertrand Dousset, Maria Candida Barisson Villares Fragoso, Patricia Vaduva, Constantine A. Stratakis, Rossella Libé, Marie-Odile North, Mathilde Sibony, Guillaume Assié, Anne Jouinot, Eric Letouzé, Florian Violon, Eric Pasmant, Philippe Emy, Igor Tauveron, Martin Reincke, Annabel Berthon, Magalie Haissaguerre, Karine Perlemoine, Fidéline Bonnet, Christopher Ribes, Isadora Cavalcante, Laurence Guignat, Lucas Bouys, Jérôme Bertherat, Lionel Groussin, Roberta Armignacco, Anna Vaczlavik, Gaetan Giannone, and Stéphanie Espiard
Subjects: History, animal structures, Polymers and Plastics, business.industry, Adrenalectomy, medicine.medical_treatment, Industrial and Manufacturing Engineering, Germline, Macronodular Adrenal Hyperplasia, DNA methylation, Cancer research, Medicine, Ectopic expression, Business and International Management, Allele, business, Exome sequencing, SNP array
Abstract: Purpose: To investigate the genetic cause of Food-dependent Cushing’s syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the GIP receptor (GIPR). Germline ARMC5 alterations have been reported in about 25 % of PBMAH index cases but are absent in patients with FDCS. Methods: A multi-omics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNAseq, SNP array, methylome, miRNome, exome sequencing). Results: The integrative analysis revealed three molecular groups with different clinical features: G1, PBMAH due to ARMC5 inactivating variants; G2, with GIPR ectopic expression and FDCS; and G3, with a less severe phenotype. Exome sequencing revealed germline truncating variants of LSD1/KDM1A in the G2 group, constantly associated with a somatic loss of the LSD1/KDM1A wildtype allele on 1p, leading to a loss of LSD1/KDM1A expression both at mRNA and protein levels (p=1.2x10-12 and p
Published: 2021
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28. 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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29. Identification of clinical parameters predictive of ARMC5 mutation in a large cohort of primary bilateral macronodular adrenal hyperplasia (PBMAH) patients

Author: Laurence Guignat, Antoine Tabarin, Jean-Louis Sadoul, Rossella Libe, Marie-Odile North, Françoise Borson-Chazot, Wiebke Arlt, Marie-Christine Vantyghem, Lefebvre Hervé, Felix Beuschlein, Patricia Vaduva, Lionel Groussin, Stéphanie Espiard, Anna Angelousi, Karine Perlemoine, Anna Vaczlavik, Trevor Cole, Chabre Olivier, Guillaume Assié, Christin-Maitre Sophie, Ana Agapito, Jérôme Bertherat, Marie-Laure Raffin-Sanson, Lucas Bouys, Philippe Chanson, Thierry Brue, Matthias Kroiss, Marcus Quinkler, Martin Reincke, and Bruno Ragazzon
Subjects: Oncology, medicine.medical_specialty, business.industry, Macronodular Adrenal Hyperplasia, Internal medicine, Mutation (genetic algorithm), Medicine, Identification (biology), business, Large cohort
Published: 2020
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30. 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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31. 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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32. 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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33. Integrated genomics reveals different subgroups of primary bilateral macronodular adrenal hyperplasia (PBMAH)

Author: Franck Letourneur, Lucas Bouys, Mathilde Sibony, Bruno Ragazzon, Fidéline Bonnet, Jérôme Bertherat, Guillaume Assié, Laurence Guignat, Anna Vaczlavik, Karine Perlemoine, Stéphanie Espiard, Victor Heurtier, and Eric Letouzé
Subjects: Pathology, medicine.medical_specialty, business.industry, Macronodular Adrenal Hyperplasia, Medicine, Genomics, business
Published: 2020
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34. 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

35. 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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36. Hétérogénéité morphologique des hyperplasies macronodulaires bilatérales primitives des surrénales

Author: L. Guignat, F. Violon, Anna Vaczlavik, Guillaume Assié, A. Berthon, Karine Perlemoine, Benoit Terris, Bruno Ragazzon, Jérôme Bertherat, L. Groussin, Lucas Bouys, and Mathilde Sibony
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Published: 2021
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37. L’étude génomique de l’hyperplasie macronodulaire bilatérale primitive des surrénales (HMBPS) révèle 3 groupes aux caractéristiques clinico-pathologiques distinctes, un lié à ARMC5 et un deuxième à un nouveau gène responsable du syndrome de Cushing dépendant de l’alimentation : LSD1/KDM1A, étendant le spectre des causes génétiques du syndrome de Cushing surrénalien

Author: C. Ribes, Eric Pasmant, Maria Candida Barisson Villares Fragoso, Herve Lefebvre, Lucas Bouys, Igor Tauveron, Isadora Pontes Cavalcante, Karine Perlemoine, P. Vaduva, F. Bonnet, Marie-Odile North, M. Barat, G. Giannone, Mathilde Sibony, Eric Letouzé, Anna Vaczlavik, Roberta Armignacco, Martin Reincke, Jérôme Bertherat, F. Violon, A. Berthon, C. A. Stratakis, Guillaume Assié, L. Groussin, Anne Jouinot, R. Libe, Bertrand Dousset, Philippe Emy, Bruno Ragazzon, L. Guignat, Magalie Haissaguerre, and Stéphanie Espiard
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Published: 2021
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38. ARMC5 mutation in a Portuguese family with primary bilateral macronodular adrenal hyperplasia (PBMAH)

Author: Ana Agapito, Jérôme Bertherat, Karine Perlemoine, Fernando Fonseca, Stéphanie Espiard, and Teresa Rego
Subjects: Pathology, medicine.medical_specialty, Pediatrics, Endocrinology, Diabetes and Metabolism, Fludrocortisone, 030209 endocrinology & metabolism, Disease, 030204 cardiovascular system & hematology, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Cushing syndrome, 0302 clinical medicine, Germline mutation, Internal Medicine, medicine, Hydrocortisone, Insight into Disease Pathogenesis or Mechanism of Therapy, Hyperplasia, lcsh:RC648-665, Portugal, Adrenal gland, business.industry, medicine.disease, 3. Good health, medicine.anatomical_structure, Macronodular Adrenal Hyperplasia, Mutation, Etiology, business, HCC END, medicine.drug
Abstract: Summary PBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH Learning points: PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion. The asymmetric/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge. Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely. As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.
Published: 2017
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39. Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma

Author: Joël Coste, Antoine Tabarin, Karine Perlemoine, Louis Jacob, Ronald R. de Krijger, Simon Garinet, Jens Waldmann, Olivier Chabre, Mathilde Sibony, Felix Beuschlein, Magalie Haissaguerre, Bertrand Dousset, Nadim Hamzaoui, Bruno de La Villéon, Bruno Ragazzon, Anne Jouinot, Laurence Amar, Martin Fassnacht, Esther Korpershoek, Massimo Mannelli, Xavier Bertagna, Rossella Libé, Marcus Quinkler, Frédérique Tissier, Guillaume Assié, Jérôme Bertherat, Matthias Kroiss, Julien Sakat, Lionel Groussin, Eric Baudin, Michaela Luconi, Cristina L Ronchi, Silviu Sbiera, Mario Neou, Sébastien Gaujoux, and Pathology
Subjects: Oncology, medicine.medical_specialty, Cancer Research, Mitotic index, Proliferation index, business.industry, Hazard ratio, medicine.disease, BUB1B, 03 medical and health sciences, GSTP1, 0302 clinical medicine, Interquartile range, 030220 oncology & carcinogenesis, Internal medicine, medicine, Adjuvant therapy, Adrenocortical carcinoma, 030212 general & internal medicine, business, Original Investigation
Abstract: IMPORTANCE: The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome. OBJECTIVE: To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018. EXPOSURES: Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts. MAIN OUTCOMES AND MEASURES: Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model. RESULTS: Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P
Published: 2019

40. 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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41. 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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42. 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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43. 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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44. Génomique intégrée des Hyperplasies Macronodulaires Bilatérales primitives des Surrénales (HMBS)

Author: Stéphanie Espiard, Fabrice Bonnet, Franck Letourneur, Jérôme Bertherat, V. Heurtier, Guillaume Assié, L. Bouys, A. Vaczlavik, L. Guignat, Bruno Ragazzon, Karine Perlemoine, and Eric Letouzé
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Introduction Le spectre clinique de l’hyperplasie macronodulaire bilaterale primitive des surrenales (HMBPS) est large. La secretion de cortisol peut etre mediee par des recepteurs illegitimes a l’ACTH dont le GIP-R, responsable de syndromes de Cushing dependants de l’alimentation. Des mutations germinales inactivatrices d’ARMC5 sont identifiees dans 20 % des cas. Objectif Caracteriser les alterations moleculaires dans les HMBS. Methodes Extractions des acides des tissus d’HMBS congeles de 36 patients surrenalectomises (oncotheque COMETE) ; 15/36 patients mutes pour ARMC5. Analyse des alterations du nombre de copie (Illumina HumanCore BeadChips, 306.702 SNPs). Etude dy profil de methylation tumoral (Illumina MethylationEPIC BeadChip array, 866.895 sondes). Sequencage Illumina des ARN et miARN (Genomic, Institut Cochin). Resultats Pas d’alteration chromosomique dans la moitie des echantillons. Perte d’heterozygtie sans alteration du nombre de copie en 16p observee chez 6 patients mutes ARMC5. Ont aussi ete mis en evidence : gain en 1q (n = 5) ; gain en 9q21.11–9q34.3 (n = 3, locus SF1). L’etude des 5000 positions les plus differentiellement methylees a permis d’etablir 2 groupes correspondant au statut ARMC5. Un profil micro ARN specifique a ete observe pour les tumeurs ARMC5 mutes. L’analyse du transcriptome differencie les tumeurs ARMC5 mutees des autres. Parmi les tumeurs ARMC5 sauvage, un sous-groupe se distingue par la surexpression du GIPR (fold change 5.8, p = 5.7E–09). Conclusion Cette premiere analyse de genomique integree dans l’HMBPS reflete l’heterogeneite clinique au niveau moleculaire. Elle distingue 3 groupes dont l’un est conduit par la mutation ARMC5,un autre caracterise par la surexpression du GIPR. Le troisieme doit etre etudie.
Published: 2020
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45. Identification de paramètres cliniques prédictifs d’une mutation d’ARMC5 dans une grande cohorte de patients porteurs d’Hyperplasie Macronodulaire Bilatérale des Surrénales (HMBS)

Author: Jérôme Bertherat, R. Libe, A. Agapito, Ph. Chanson, L. Guignat, Karine Perlemoine, T. Cole, Matthias Kroiss, Nicolas Chevalier, Lucas Bouys, P. Vaduva, S. Christin-Maitre, A. Tabarin, Anna Angelousi, T. Brue, Philippe Touraine, Guillaume Assié, Marie-Christine Vantyghem, Marie-Laure Raffin-Sanson, F Beuschlein, Herve Lefebvre, Marcus Quinkler, F. Borson-Chazot, Bruno Ragazzon, Martin Reincke, Olivier Chabre, L. Groussin, Anna Vaczlavik, Wiebke Arlt, Stéphanie Espiard, and Marie-Odile North
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: Introduction L’HMBS est une pathologie rare et heterogene, caracterisee par de multiples macronodules surrenaliens, responsables d’un hypercortisolisme d’intensite variable. La moitie des patients avec forme severe, traites par surrenalectomie bilaterale, presente une mutation germinale inactivatrice heterozygote du gene suppresseur de tumeurs ARMC5, et 80 % pour les formes clairement familiales, contre seulement 20 % des formes sporadiques. L’objectif de cette etude etait d’etablir des criteres predictifs de mutation d’ARMC5. Methodes 454 cas index francais et europeens porteurs d’HMBS ont ete genotypes pour ARMC5 a Cochin. Parmi ces 454 patients, nous avons analyse retrospectivement les donnees cliniques, radiologiques et biologiques de 264 patients suivis dans cinq services d’endocrinologie universitaires francais (reseau COMETE). Resultats 40 cas index sur les 264 analyses (15,2 %) presentent une mutation germinale inactivatrice d’ARMC5, coherent avec le taux de mutation observe dans la cohorte de 454 patients (14,3 %). Les patients mutes ont une pathologie plus severe que les patients non-mutes, en termes d’intensite de l’hypercortisolisme biologique, de morphologie surrenalienne et de complications. 100 % des patients mutes presentent des nodules surrenaliens bilateraux ET un cortisol plasmatique apres freinage minute a la dexamethasone superieur a 50 nmol/L, alors que seulement 61,6 % des patients non-mutes ont l’association de ces deux criteres. Du fait de sa valeur predictive negative de 100 %, l’absence de cette association permet d’exclure une mutation d’ARMC5. Conclusion Restreindre l’indication du sequencage d’ARMC5 aux patients presentant des nodules surrenaliens bilateraux et une secretion autonome de cortisol permettrait d’eviter un genotypage negatif chez un tiers des patients sans perte de sensibilite.
Published: 2020
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46. MET overexpression and activation favors invasiveness in a model of anaplastic thyroid cancer

Author: Cyril, Garcia, Camille, Buffet, Laila, El Khattabi, Marthe, Rizk-Rabin, Karine, Perlemoine, Bruno, Ragazzon, Jérôme, Bertherat, Françoise, Cormier, and Lionel, Groussin
Subjects: MET targeting, thyroid cancer, PHA665752, cell invasion, MET amplification, Research Paper
Abstract: In thyroid cancers, MET receptor overexpression has been associated with higher risk of metastatic progression. In this study, it was shown that the anaplastic thyroid cancer (ATC)-derived TTA1 cell line overexpressed MET. By using FISH and relative quantification by qPCR, it was demonstrated that this overexpression resulted from a MET amplification with more than 20 copies. As expected, MET overexpression led to its constitutive activation and upregulated signaling towards the MAPK, PI3K/AKT, STAT3 and NF-κB pathways. Since the usual feature of MET-amplified cell lines is the "MET addiction" for their cell proliferation, the effect of the highly selective ATP competitive MET inhibitor PHA665752 was analyzed. While PHA665752 strongly inhibited the MAPK pathway, it did not reduce cell proliferation in TTA1 cells (IC50 = 4100 nM). This resistance to PHA665752 of the TTA1 cell line was demonstrated to be related to EGFR-MET functional cross-talk and PI3K/AKT and NF-κB signaling. Nevertheless, PHA665752 suppressed the anchorage-independent growth capacity of the TTA1 cell line and reduced cell migration and invasion in a transwell assay. The role of activated MET in these neoplastic properties of the TTA1 cells was also proved with si-MET-RNA targeting. Thus, this work highlights the TTA1 cell line as the first model of MET amplification in an ATC cell line, which leads to MET constitutive activation and underlies its neoplastic properties. Besides being a useful model for MET inhibitors screening, the TTA1 cell line also supports the argument for searching for MET amplification in ATC, as it could have therapeutic implications.
Published: 2018

47. Molecular classification of benign adrenocortical tumors: an integrated genomic study

Author: Marthe Rizk-Rabin, Anna Vaczlavik, Lionel Groussin, Stéphanie Espiard, Frédérique Tissier, Windy Luscap-Rondof, Jérôme Bertherat, S. Faillot, Mario Neou, Guillaume Assié, Simon Garinet, Ludivine Drougat, Rossella Libé, Fernande René-Corail, Anne Jouinot, Karine Perlemoine, Reynies Aurelien de, and Bruno Ragazzon
Subjects: Molecular classification, Computational biology, Biology
Published: 2018
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48. Identification of new ARMC5 missense mutations in Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) and their functional studies in vitro

Author: Bruno Ragazzon, Stéphanie Espiard, Ludivine Drougat, Marthe Rizk-Rabin, Anna Vaczlavik, Karine Perlemoine, Marie-Odile North, and Jérôme Bertherat
Subjects: Primary (chemistry), business.industry, Macronodular Adrenal Hyperplasia, Cancer research, Missense mutation, Medicine, Identification (biology), Functional studies, business, In vitro
Published: 2018
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49. Molecular classifiers refine the prognostic stratification of adrenocortical carcinoma

Author: Esther Korpershoek, Xavier Bertagna, Mario Neou, Olivier Chabre, Simon Faillot, Matthias Kroiss, Mathilde Sibony, Karine Perlemoine, Marcus Quinkler, Lionel Groussin, Julien Sakat, Frédérique Tissier, Massimo Mannelli, Guillaume Assié, Laurence Amar, Krijger Ronald De, Antoine Tabarin, Rossella Libe, Nadim Hamzaoui, Anne Jouinot, Silviu Sbiera, Joel Coste, Jens Waldmann, Michaela Luconi, Cristina L Ronchi, Bertrand Dousset, Jérôme Bertherat, Louis Jacob, Felix Beuschlein, Eric Baudin, Martin Fassnacht, and Simon Garinet
Subjects: Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine, Adrenocortical carcinoma, medicine.disease, business, Prognostic stratification
Published: 2018
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50. Detection and monitoring of circulating tumor DNA in adrenocortical carcinoma

Author: Mario Neou, Olivier Soubrane, Guillaume Assié, Lucie Orhant, Juliana Pipoli da Fonseca, Franck Letourneur, Jérôme Bertherat, Anne Jouinot, Eric Pasmant, Lionel Groussin, Rossella Libé, Bertrand Dousset, Juliette Nectoux, Karine Perlemoine, Léopoldine Bricaire, Simon Garinet, Mathilde Sibony, Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de chirurgie hepato-pancreato-biliaire, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut Cochin (UMR_S567 / UMR 8104), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Sequence analysis, Endocrinology, Diabetes and Metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Circulating Tumor DNA, 03 medical and health sciences, chemistry.chemical_compound, Endocrinology, X ray computed, Adrenocortical Carcinoma, Medicine, Adrenocortical carcinoma, Humans, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, business.industry, Sequence Analysis, DNA, Middle Aged, medicine.disease, Adrenal Cortex Neoplasms, 030104 developmental biology, Oncology, chemistry, Circulating tumor DNA, Cancer research, Female, business, Tomography, X-Ray Computed, DNA
Abstract: International audience
Published: 2018
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