Filter

Refine by collections

Refine by date

—

Refine by access

  • Print
  • Save

Search Results

You are looking at 1 - 8 of 8 items for

  • Author: Guillaume Assié x
  • Refine by access: All content x
Clear All Modify Search
Bruno Ragazzon Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France

Search for other papers by Bruno Ragazzon in
Google Scholar
PubMed Close
,
Guillaume Assié Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France

Search for other papers by Guillaume Assié in
Google Scholar
PubMed Close
, and
Jérôme Bertherat Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France

Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed Close

Transcriptome analysis has been successfully used to study the gene profile expression of adrenocortical tumors (ACT) for 7 years. The various studies reported to date have produced an abundance of new information on adrenocortical cancer (ACC), underlying the validity of this approach to study the molecular genetics and pathogenesis of these tumors. The gene expression profile of ACC clearly differs from that of benign adrenocortical adenomas (ACA). Interestingly, transcriptome analysis has the ability to establish a subclassification of ACC based on the gene expression profile. In particular, it is able to identify two groups of tumors with different outcomes (i.e. good prognosis and poor prognosis). This approach has been used to develop molecular markers for ACC diagnosis and prognostication. An IGF2 cluster of genes up-regulated in ACC has been identified. Transcriptome analysis has shown that, in comparison with ACA, IGF2 is indeed the gene most overexpressed in ACC. By contrast, genes associated with steroidogenesis are down-regulated in ACC. Genes controlling the cell cycle are dysregulated in ACC, and several are dramatically overexpressed. Analysis regarding the level of expression of Wnt/β-catenin and p53 signaling has shown alterations, in keeping with the known molecular somatic genetic defects of these pathways that are observed in ACC. This review summarizes the main findings of studies reporting ACC transcriptome analysis, demonstrating its power for ACT classification, and examines the resulting progress in understanding the pathogenesis of ACC. The potential for both ACC diagnosis and the identification of new therapeutic targets will be discussed.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/ERC-10-0220
Volume/Issue:
Volume 18: Issue 2
Free access
Chiara Villa Department of Neuropathology, Hôpital Universitaire Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France
Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes-Université de Paris, Paris, France

Search for other papers by Chiara Villa in
Google Scholar
PubMed Close
,
Bertrand Baussart Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes-Université de Paris, Paris, France
Department of Neurosurgery, Hôpital Universitaire Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France

Search for other papers by Bertrand Baussart in
Google Scholar
PubMed Close
,
Guillaume Assié Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes-Université de Paris, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin APHP, Paris, France

Search for other papers by Guillaume Assié in
Google Scholar
PubMed Close
,
Gerald Raverot Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France
Lyon 1 University, Villeurbanne, France
Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France

Search for other papers by Gerald Raverot in
Google Scholar
PubMed Close
, and
Federico Roncaroli Geoffrey Jefferson Brain Research Centre, Division of Neuroscience, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom

Search for other papers by Federico Roncaroli in
Google Scholar
PubMed Close

The classification of tumours of the pituitary gland has recently been revised in the 2021 5th edition World Health Organization (WHO) Classification of Central Nervous System Tumours (CNS5) and 2022 5th edition WHO Classification of Endocrine and Neuroendocrine Tumours (ENDO5). This brief review aims to appraise the most relevant changes and updates introduced in the two classifications. A new nomenclature has been introduced in CNS5 and ENDO5 to align adenohypophyseal tumours with the classification framework of neuroendocrine neoplasia. The term pituitary neuroendocrine tumour (PitNET) with subtype information has therefore been adopted and preferred to adenoma. Pituitary carcinoma has been replaced by metastatic PitNET. The ICD-O coding has been changed from benign to malignant in line with NETs from other organs. Histological typing and subtyping based on immunohistochemistry for lineage-restricted pituitary transcription factors are regarded as the cornerstone for accurate classification. Such an approach does not fully reflect the complexity and dynamics of pituitary tumorigenesis and the variability of transcription factors expression. ENDO5 does not support a grading and/or staging system and argues that histological typing and subtyping are more robust than proliferation rate and invasiveness to stratify tumours with low or high risk of recurrence. However, the prognostic and predictive relevance of histotype is not fully validated. Recent studies suggest the existence of clinically relevant molecular subgroups and emphasize the need for a standardized, histo-molecular integrated approach to the diagnosis of PitNETs to further our understanding of their biology and overcome the unsolved issue of grading and/or staging system.

Article Type:
Review Article
Collections:
Mini Reviews in Endocrine Related Cancer
DOI:
https://doi.org/10.1530/ERC-23-0021
Volume/Issue:
Volume 30: Issue 8
Free access
Marc Diedisheim Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Diabetology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Marc Diedisheim in
Google Scholar
PubMed Close
,
Solène Dermine Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Gastroenterology and Digestive Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Solène Dermine in
Google Scholar
PubMed Close
,
Anne Jouinot Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Anne Jouinot in
Google Scholar
PubMed Close
,
Amandine Septier Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France

Search for other papers by Amandine Septier in
Google Scholar
PubMed Close
,
Sébastien Gaujoux Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Digestive Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Sébastien Gaujoux in
Google Scholar
PubMed Close
,
Bertrand Dousset Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Digestive Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Bertrand Dousset in
Google Scholar
PubMed Close
,
Guillaume Cadiot Department of Gastroenterology, Robert-Debré Hospital, Reims, France

Search for other papers by Guillaume Cadiot in
Google Scholar
PubMed Close
,
Etienne Larger Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Diabetology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Etienne Larger in
Google Scholar
PubMed Close
,
Jérôme Bertherat Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed Close
,
Raphael Scharfmann Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France

Search for other papers by Raphael Scharfmann in
Google Scholar
PubMed Close
,
Benoit Terris Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Benoit Terris in
Google Scholar
PubMed Close
,
Romain Coriat Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Gastroenterology and Digestive Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Romain Coriat in
Google Scholar
PubMed Close
, and
Guillaume Assié Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Search for other papers by Guillaume Assié in
Google Scholar
PubMed Close

Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular updates changing the definition of classes. Genomic screening may provide more objective classes and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcomes (log-rank P < 0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the topmost expressed liver genes. FGA expression was associated with disease-free survival (HR = 1.13, P = 0.005) and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/ERC-21-0051
Volume/Issue:
Volume 28: Issue 8
Restricted access
Simon Garinet Institut Cochin INSERM U1016/UMR8104 and CNRS UMR-S8104, Paris, France

Search for other papers by Simon Garinet in
Google Scholar
PubMed Close
,
Juliette Nectoux Laboratory of Genetics and Molecular Biology, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Juliette Nectoux in
Google Scholar
PubMed Close
,
Mario Neou Institut Cochin INSERM U1016/UMR8104 and CNRS UMR-S8104, Paris, France

Search for other papers by Mario Neou in
Google Scholar
PubMed Close
,
Eric Pasmant Laboratory of Genetics and Molecular Biology, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Paris, France
INSERM UMR745, Biological and Pharmaceutical Sciences University, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Search for other papers by Eric Pasmant in
Google Scholar
PubMed Close
,
Anne Jouinot Institut Cochin INSERM U1016/UMR8104 and CNRS UMR-S8104, Paris, France
Department of Medical Oncology, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Anne Jouinot in
Google Scholar
PubMed Close
,
Mathilde Sibony Department of Pathology, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Mathilde Sibony in
Google Scholar
PubMed Close
,
Lucie Orhant Laboratory of Genetics and Molecular Biology, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Lucie Orhant in
Google Scholar
PubMed Close
,
Juliana Pipoli da Fonseca Institut Cochin GENOMI’C Platform, Paris, France

Search for other papers by Juliana Pipoli da Fonseca in
Google Scholar
PubMed Close
,
Karine Perlemoine Institut Cochin INSERM U1016/UMR8104 and CNRS UMR-S8104, Paris, France

Search for other papers by Karine Perlemoine in
Google Scholar
PubMed Close
,
Léopoldine Bricaire Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Léopoldine Bricaire in
Google Scholar
PubMed Close
,
Lionel Groussin Institut Cochin INSERM U1016/UMR8104 and CNRS UMR-S8104, Paris, France
Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Lionel Groussin in
Google Scholar
PubMed Close
,
Olivier Soubrane Department of Hepato-Pancreato-Biliary Surgery, Hôpital Beaujon, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Olivier Soubrane in
Google Scholar
PubMed Close
,
Bertrand Dousset Department of Digestive and Endocrine Surgery, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Bertrand Dousset in
Google Scholar
PubMed Close
,
Rossella Libe Institut Cochin INSERM U1016/UMR8104 and CNRS UMR-S8104, Paris, France
Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France

Search for other papers by Rossella Libe in
Google Scholar
PubMed Close
,
Franck Letourneur Institut Cochin GENOMI’C Platform, Paris, France

Search for other papers by Franck Letourneur in
Google Scholar
PubMed Close
,
Jérome Bertherat Institut Cochin INSERM U1016/UMR8104 and CNRS UMR-S8104, Paris, France
Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
Reference Center for Rare Adrenal Diseases, Reference Center for Rare Adrenal Cancer Network COMETE, Hôpital Cochin, AssistancePublique – Hôpitaux de Paris, Paris, France

Search for other papers by Jérome Bertherat in
Google Scholar
PubMed Close
, and
Guillaume Assié Institut Cochin INSERM U1016/UMR8104 and CNRS UMR-S8104, Paris, France
Department of Endocrinology, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
Reference Center for Rare Adrenal Diseases, Reference Center for Rare Adrenal Cancer Network COMETE, Hôpital Cochin, AssistancePublique – Hôpitaux de Paris, Paris, France

Search for other papers by Guillaume Assié in
Google Scholar
PubMed Close
Article Type:
Letter
DOI:
https://doi.org/10.1530/ERC-17-0467
Volume/Issue:
Volume 25: Issue 3
Free access
Florian Haller
Search for other papers by Florian Haller in
Google Scholar
PubMed Close
,
Evgeny A Moskalev
Search for other papers by Evgeny A Moskalev in
Google Scholar
PubMed Close
,
Fabio R Faucz Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Fabio R Faucz in
Google Scholar
PubMed Close
,
Sarah Barthelmeß
Search for other papers by Sarah Barthelmeß in
Google Scholar
PubMed Close
,
Stefan Wiemann Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Stefan Wiemann in
Google Scholar
PubMed Close
,
Matthias Bieg Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Matthias Bieg in
Google Scholar
PubMed Close
,
Guillaume Assie Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Guillaume Assie in
Google Scholar
PubMed Close
,
Jerome Bertherat Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Jerome Bertherat in
Google Scholar
PubMed Close
,
Inga-Marie Schaefer Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Inga-Marie Schaefer in
Google Scholar
PubMed Close
,
Claudia Otto Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Claudia Otto in
Google Scholar
PubMed Close
,
Eleanor Rattenberry Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Eleanor Rattenberry in
Google Scholar
PubMed Close
,
Eamonn R Maher Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Eamonn R Maher in
Google Scholar
PubMed Close
,
Philipp Ströbel Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Philipp Ströbel in
Google Scholar
PubMed Close
,
Martin Werner Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Martin Werner in
Google Scholar
PubMed Close
,
J Aidan Carney Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by J Aidan Carney in
Google Scholar
PubMed Close
,
Arndt Hartmann
Search for other papers by Arndt Hartmann in
Google Scholar
PubMed Close
,
Constantine A Stratakis Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany

Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Division Molecular Genome Analysis

Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany

Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany

Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany

School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK

Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK

Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Constantine A Stratakis in
Google Scholar
PubMed Close
, and
Abbas Agaimy
Search for other papers by Abbas Agaimy in
Google Scholar
PubMed Close

Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney–Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/ERC-14-0254
Volume/Issue:
Volume 21: Issue 4
Free access
Laura C Hernández-Ramírez Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

Search for other papers by Laura C Hernández-Ramírez in
Google Scholar
PubMed Close
,
Ryhem Gam Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada

Search for other papers by Ryhem Gam in
Google Scholar
PubMed Close
,
Nuria Valdés Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain

Search for other papers by Nuria Valdés in
Google Scholar
PubMed Close
,
Maya B Lodish Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

Search for other papers by Maya B Lodish in
Google Scholar
PubMed Close
,
Nathan Pankratz Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

Search for other papers by Nathan Pankratz in
Google Scholar
PubMed Close
,
Aurelio Balsalobre Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada

Search for other papers by Aurelio Balsalobre in
Google Scholar
PubMed Close
,
Yves Gauthier Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada

Search for other papers by Yves Gauthier in
Google Scholar
PubMed Close
,
Fabio R Faucz Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

Search for other papers by Fabio R Faucz in
Google Scholar
PubMed Close
,
Giampaolo Trivellin Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

Search for other papers by Giampaolo Trivellin in
Google Scholar
PubMed Close
,
Prashant Chittiboina Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA

Search for other papers by Prashant Chittiboina in
Google Scholar
PubMed Close
,
John Lane Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

Search for other papers by John Lane in
Google Scholar
PubMed Close
,
Denise M Kay Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, New York, USA

Search for other papers by Denise M Kay in
Google Scholar
PubMed Close
,
Aggeliki Dimopoulos Division of Intramural Population Health Research, Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

Search for other papers by Aggeliki Dimopoulos in
Google Scholar
PubMed Close
,
Stephan Gaillard Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France
Department of Neurosurgery, Hôpital Foch, Suresnes, France

Search for other papers by Stephan Gaillard in
Google Scholar
PubMed Close
,
Mario Neou Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France

Search for other papers by Mario Neou in
Google Scholar
PubMed Close
,
Jérôme Bertherat Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France
Service d’Endocrinologie, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed Close
,
Guillaume Assié Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France
Service d’Endocrinologie, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

Search for other papers by Guillaume Assié in
Google Scholar
PubMed Close
,
Chiara Villa Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France
Department of Pathological Cytology and Anatomy, Hôpital Foch, Suresnes, France
Department of Endocrinology, CHU de Liège, University of Liège, Liège, Belgium

Search for other papers by Chiara Villa in
Google Scholar
PubMed Close
,
James L Mills Division of Intramural Population Health Research, Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

Search for other papers by James L Mills in
Google Scholar
PubMed Close
,
Jacques Drouin Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada

Search for other papers by Jacques Drouin in
Google Scholar
PubMed Close
, and
Constantine A Stratakis Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

Search for other papers by Constantine A Stratakis in
Google Scholar
PubMed Close

The CABLES1 cell cycle regulator participates in the adrenal–pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing’s disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/ERC-17-0131
Volume/Issue:
Volume 24: Issue 8
Open access
Simon Faillot Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Simon Faillot in
Google Scholar
PubMed Close
,
Thomas Foulonneau Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Thomas Foulonneau in
Google Scholar
PubMed Close
,
Mario Néou Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Mario Néou in
Google Scholar
PubMed Close
,
Stéphanie Espiard Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Stéphanie Espiard in
Google Scholar
PubMed Close
,
Simon Garinet Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Simon Garinet in
Google Scholar
PubMed Close
,
Anna Vaczlavik Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Anna Vaczlavik in
Google Scholar
PubMed Close
,
Anne Jouinot Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Anne Jouinot in
Google Scholar
PubMed Close
,
Windy Rondof Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Windy Rondof in
Google Scholar
PubMed Close
,
Amandine Septier Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Amandine Septier in
Google Scholar
PubMed Close
,
Ludivine Drougat Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Ludivine Drougat in
Google Scholar
PubMed Close
,
Karine Hécale-Perlemoine Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Karine Hécale-Perlemoine in
Google Scholar
PubMed Close
,
Bruno Ragazzon Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Bruno Ragazzon in
Google Scholar
PubMed Close
,
Marthe Rizk-Rabin Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

Search for other papers by Marthe Rizk-Rabin in
Google Scholar
PubMed Close
,
Mathilde Sibony Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Pathology, AP-HP, Hôpital Pitié-Salpétrière, Pierre et Marie Curie Université, Paris, France

Search for other papers by Mathilde Sibony in
Google Scholar
PubMed Close
,
Fidéline Bonnet-Serrano Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France
Department of Hormonology, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Fidéline Bonnet-Serrano in
Google Scholar
PubMed Close
,
Jean Guibourdenche Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Hormonology, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Jean Guibourdenche in
Google Scholar
PubMed Close
,
Rosella Libé Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Rosella Libé in
Google Scholar
PubMed Close
,
Lionel Groussin Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Lionel Groussin in
Google Scholar
PubMed Close
,
Bertrand Dousset Department of Endocrine Surgery, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Bertrand Dousset in
Google Scholar
PubMed Close
,
Aurélien de Reyniès Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France

Search for other papers by Aurélien de Reyniès in
Google Scholar
PubMed Close
,
Jérôme Bertherat Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed Close
, and
Guillaume Assié Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Guillaume Assié in
Google Scholar
PubMed Close

Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/ERC-20-0128
Volume/Issue:
Volume 28: Issue 1
Restricted access
Fabio R Faucz Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

Search for other papers by Fabio R Faucz in
Google Scholar
PubMed Close
,
Anelia D Horvath Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia, United States of America

Search for other papers by Anelia D Horvath in
Google Scholar
PubMed Close
,
Guillaume Assié Université Paris Cité, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France
Endocrine Department, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Guillaume Assié in
Google Scholar
PubMed Close
,
Madson Q Almeida Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
Adrenal Unit, Laboratory of Molecular and Cellular Endocrinology LIM/25, Division of Endocrinology and Metabolism, University of Sao Paulo Medical School, São Paulo, Brasil

Search for other papers by Madson Q Almeida in
Google Scholar
PubMed Close
,
Eva Szarek Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

Search for other papers by Eva Szarek in
Google Scholar
PubMed Close
,
Sosipatros Boikos Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

Search for other papers by Sosipatros Boikos in
Google Scholar
PubMed Close
,
Anna Angelousi Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

Search for other papers by Anna Angelousi in
Google Scholar
PubMed Close
,
Isaac Levy Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

Search for other papers by Isaac Levy in
Google Scholar
PubMed Close
,
Andrea G Maria Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

Search for other papers by Andrea G Maria in
Google Scholar
PubMed Close
,
Ajay Chitnis Laboratory of Molecular Genetics, Section on Neural Developmental Dynamics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

Search for other papers by Ajay Chitnis in
Google Scholar
PubMed Close
,
Cristina R Antonescu Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America

Search for other papers by Cristina R Antonescu in
Google Scholar
PubMed Close
,
Rainer Claus Hematology and Oncology, Medical Faculty, University of Augsburg, Augsburg, Germany

Search for other papers by Rainer Claus in
Google Scholar
PubMed Close
,
Jérôme Bertherat Université Paris Cité, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France
Endocrine Department, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

Search for other papers by Jérôme Bertherat in
Google Scholar
PubMed Close
,
Christoph Plass Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany

Search for other papers by Christoph Plass in
Google Scholar
PubMed Close
,
Charis Eng Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America

Search for other papers by Charis Eng in
Google Scholar
PubMed Close
, and
Constantine A Stratakis Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
Human Genetics & Precision Medicine, IMBB, Foundation for Research & Technology Hellas, Heraklion, Crete, Greece
Research Institute, ELPEN, Pikermi, Athens, Greece

Search for other papers by Constantine A Stratakis in
Google Scholar
PubMed Close

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as ‘Genesis’ and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/ERC-23-0067
Volume/Issue:
Volume 30: Issue 10
Restricted access