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1. EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity

Author

Anne-Isabelle Bertozzi, Emmanuelle Uro-Coste, Claude-Alain Maurage, Sarah Péricart, Sergio Boetto, Yvan Nicaise, Sophie Le Guellec, Camille Franchet, Alix Delrieu, Matthieu Vinchon, David Grand, Frédéric Escudié, David T.W. Jones, Valérie Rigau, Anne Gomez-Brouchet, Aurore Siegfried, Jean-Christophe Sol, Audrey Rousseau, Franck-Emmanuel Roux, Dominique Figarella-Branger, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Pathologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pathologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Claudius-Regaud [IUCT, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Département de Neurochirurgie [CHU Toulouse], Département de Neurochirurgie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Département de Pathologie [Centre Médical Universitaire Montpellier], Centre Médical Universitaire Montpellier - CMUM, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncopédiatrie [CHU Toulouse], Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], Division of Pediatric Neurooncology [Heidelberg, Germany], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-German Cancer Consortium [Heidelberg] (DKTK), Département de Pathologie [CHU Marseille], CHU Marseille, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), D. Jones is supported by funding for the Everest Centre for Paediatric Low- Grade Brain Tumour Research through the Brain Tumour Charity (UK). We are grateful to Karen Silva for her help in handling tumor samples from the different pathological departments. Samples from Marseille were retrieved from the AP-HM tumor bank AC 2017:1786. Samples from Toulouse were retrieved from the CHU de Toulouse tumor bank BB-0033-00014., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Neurochirurgie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Bernardo, Elizabeth, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopp Children's Cancer Center at the NCT Heidelberg - KiTZ [Heidelber, Germany]g, Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre hospitalier universitaire d'Angers ( CHU Angers ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille ( U837 INSERM - IRCL ), Institut pour la recherche sur le cancer de Lille [Lille] ( IRCL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Universitaire du Cancer Toulouse - Oncopôle ( IUCT ), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Toulouse Neuro Imaging Center ( ToNIC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse-Université Toulouse III - Paul Sabatier, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), German Cancer Research Center ( DKFZ ) -German Cancer Consortium - DKTK [Heidelberg, Germany], Institut de neurophysiopathologie ( INP ), and Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
0301 basic medicine, Adult, Male, DNA Copy Number Variations, Kruppel-Like Transcription Factors, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Ganglioglioma, Fusion gene, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, medicine, Biomarkers, Tumor, Humans, Copy-number variation, Child, In Situ Hybridization, Fluorescence, Research Articles, Sanger sequencing, Brain Neoplasms, General Neuroscience, Methylation, DNA Methylation, medicine.disease, Neoplasms, Neuroepithelial, 3. Good health, Repressor Proteins, 030104 developmental biology, Fusion transcript, Cancer research, symbols, Female, Neurology (clinical), Gene Fusion, RNA-Binding Protein EWS, 030217 neurology & neurosurgery
Abstract

International audience; We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1-PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1-PATZ1 fusion transcript. RT-PCR followed by Sanger sequencing confirmed the EWSR1-PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N terminal transcriptional activation domain of EWSR1 gene and the C terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB-ZF (broad-complex, tramtrack and bric-à-brac -zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAF[V600E] negative ganglioglioma, the second a BRAF[V600E] negative glioneuronal tumor, not otherwise specified, and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAF[V600E] negative gangliogliomas were screened by FISH using EWSR1 break-apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well-defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1-PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.

Published
2019
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2. Vaginal mucosal homeostatic response may determine pregnancy outcome in women with bacterial vaginosis a pilot study

Author

Emmanuel Faure, Bruno Grandbastien, Céline Villenet, Eric Kipnis, Martin Figeac, Teddy Grandjean, Sylvain Dubucquoi, Karine Faure, Rodrigue Dessein, Damien Subtil, Gilles Brabant, Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université de Lille, Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), 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), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lille, LillOA, CHU Lille, Inserm, Recherche translationnelle : relations hôte-pathogènes - EA 7366, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Lille Inflammation Research International Center - U 995 [LIRIC], Institut pour la Recherche sur le Cancer de Lille [U837 INSERM - IRCL], and Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS]

Subjects
0301 basic medicine, MESH: Mucosal, [SDV]Life Sciences [q-bio], Physiology, 0302 clinical medicine, MESH: Pregnancy, Lactobacillus, MESH: Immunity, education.field_of_study, 030219 obstetrics & reproductive medicine, biology, General Medicine, [SDV] Life Sciences [q-bio], MESH: Infectious/immunology, MESH: Homeostasis, MESH: Pregnancy Complications, Anaerobic bacteria, Bacterial vaginosis, medicine.symptom, Population, Inflammation, MESH: Bacterial/immunology, 03 medical and health sciences, Immunity, MESH: Vaginosis, medicine, education, Pregnancy, MESH: Humans, business.industry, MESH: Adult, medicine.disease, biology.organism_classification, MESH: Pilot Projects, MESH: Pregnancy Outcome, 030104 developmental biology, Immunology, Nugent score, business, MESH: Female
Abstract

International audience; Bacterial vaginosis (BV) is considered as a trigger for an inflammatory response that could promote adverse pregnancy outcome (APO). We hypothesized that BV-related inflammation could be counterbalanced by anti-inflammatory and mucosal homeostatic responses that could participate in pregnancy outcomes.A total of 402 vaginal self-samples from pregnant women in their first trimester were screened by Nugent score. In this population, we enrolled 23 pregnant women with BV but without APO, 5 pregnant women with BV and developing APO, 21 pregnant women with intermediate flora, and 28 random control samples from pregnant women without BV or APO.BV without APO in pregnant women was associated with 28-fold interleukin-8, 5-fold interleukin-10, and 40-fold interleukin-22 increases in expression compared to controls. BV associated with APO in pregnant women shared 4-fold increase in tumor necrosis factor, 100-fold decrease in interleukin-10, and no variation in interleukin-22 expressions compared to controls. Next-generation sequencing of vaginal microbiota revealed a shift from obligate anaerobic bacteria dominance in BV without APO pregnant women to Lactobacillus dominance microbiota in BV with APO.Our results show that the anti-inflammatory and mucosal homeostatic responses to BV may determine outcome of pregnancy in the setting of BV possibly through effects on the vaginal microbiota.

Published
2016
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3. Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

Author

Andrey A. Yurchenko, Oltin T. Pop, Meriem Ighilahriz, Ismael Padioleau, Fatemeh Rajabi, Hayley J. Sharpe, Nicolas Poulalhon, Brigitte Dreno, Amir Khammari, Marc Delord, Antonio Alberti, Nadem Soufir, Maxime Battistella, Samia Mourah, Fanny Bouquet, Ariel Savina, Andrej Besse, Max Mendez-Lopez, Florent Grange, Sandrine Monestier, Laurent Mortier, Nicolas Meyer, Caroline Dutriaux, Caroline Robert, Philippe Saiag, Florian Herms, Jerome Lambert, Frederic J. de Sauvage, Nicolas Dumaz, Lukas Flatz, Nicole Basset-Seguin, Sergey I. Nikolaev, Pecqueret, Valérie, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Brustzentrum Kantonsspital St. Gallen, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The Babraham Institute [Cambridge, UK], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital de la Timone [CHU - APHM] (TIMONE), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Ambroise Paré [AP-HP], Service de Dermatologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Genentech, Inc., and Genentech, Inc. [San Francisco]

Subjects
Cancer Research, Skin Neoplasms, animal structures, integumentary system, Pyridines, [SDV]Life Sciences [q-bio], fungi, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Carcinoma, Basal Cell, Humans, Anilides, Hedgehog Proteins, Cerebellar Neoplasms
Abstract

Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.

Published
2022
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4. Alzheimer PHF-tau aggregates do not spread tau pathology to the brain via the Retino-tectal projection after intraocular injection in male mouse models

Author

M.-A. de Fisenne, Z. Yilmaz, R. De Decker, V. Suain, L. Buée, K. Ando, J.-P. Brion, K. Leroy, ULB Neuroscience Institute [Brussels] (UNI), Université libre de Bruxelles (ULB), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BUEE, Luc

Subjects
Male, Retinal Ganglion Cells, Prions, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, tau Proteins, Neurofibrillary Tangles, Mice, Transgenic, Alzheimer's disease, Retina, Mice, Disease Models, Animal, Neurology, Transgenic mouse, Alzheimer Disease, Tau pathology propagation, Animals, Humans, Intraocular injection, Injections, Intraocular
Abstract

International audience; Neurofibrillary tangles (NFT), a neuronal lesion found in Alzheimer's disease (AD), are composed of fibrillary aggregates of modified forms of tau proteins. The propagation of NFT follows neuroanatomical pathways suggesting that synaptically connected neurons could transmit tau pathology by the recruitment of normal tau in a prion-like manner. Moreover, the intracerebral injection of pathological tau from AD brains induces the seeding of normal tau in mouse brain. Creutzfeldt-Jacob disease has been transmitted after ocular transplants of cornea or sclera and the scrapie agent can spread across the retino-tectal pathway after intraocular injection of scrapie mouse brain homogenates. In AD, a tau pathology has been detected in the retina. To investigate the potential risk of tau pathology transmission during eye surgery using AD tissue material, we have analysed the development of tau pathology in the visual pathway of mice models expressing murine tau, wild-type or mutant human tau after intraocular injection of pathological tau proteins from AD brains. Although these pathological tau proteins were internalized in retinal ganglion cells, they did not induce aggregation of endogenous tau nor propagation of a tau pathology in the retino-tectal pathway after a 6-month incubation period. These results suggest that retinal ganglion cells exhibit a resistance to develop a tau pathology, and that eye surgery is not a major iatrogenic risk of transmission of tau pathology, contrary to what has been observed for transmission of infectious prions in prion diseases.

Published
2022
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5. Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa

Author

Guylène Le Meur, Susanne Roosing, Panagiotis I. Sergouniotis, Marta Corton, Sandro Banfi, Graeme C.M. Black, Ivan Conte, Hélène Naacke, Carmen Ayuso, Christian Hamel, Almudena Avila-Fernandez, Agnès Muller, Guillaume Olivier, Daniela Intartaglia, Claire-Marie Dhaenens, Gaël Manes, Sanne K Verbakel, Jeroen Klevering, Isabelle Meunier, Béatrice Bocquet, Carel B. Hoyng, Agathe Roubertie, Audrey Sénéchal, Xavier Zanlonghi, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universidad Autónoma de Madrid (UAM), CIBER de Enfermedades Raras (CIBERER), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Radboud University Medical Center [Nijmegen], Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Centre hospitalier universitaire de Nantes (CHU Nantes), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Clinique Saint-Joseph Angoulême (CSJA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac [CHU Montpellier], University of Naples Federico II = Università degli studi di Napoli Federico II, Clinique Jules-Vernes [Nantes], Hôpital Gui de Chauliac [Montpellier], Michel-Avella, Amandine, Olivier, Guillaume, Corton, Marta, Intartaglia, Daniela, Verbakel, Sanne K, Sergouniotis, Panagiotis I, Le Meur, Guylène, Dhaenens, Claire-Marie, Naacke, Hélène, Avila-Fernández, Almudena, Hoyng, Carel B, Klevering, Jeroen, Bocquet, Béatrice, Roubertie, Agathe, Sénéchal, Audrey, Banfi, Sandro, Muller, Agnè, Hamel, Christian L, Black, Graeme C, Conte, Ivan, Roosing, Susanne, Zanlonghi, Xavier, Ayuso, Carmen, Meunier, Isabelle, and Manes, Gaël

Subjects
0301 basic medicine, MESH: Extracellular Matrix Proteins, sequence analysis, [SDV]Life Sciences [q-bio], eye disease, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Benign concentric annular macular dystrophy, MESH: Eye Proteins, Missense mutation, genetics, Genetics (clinical), Exome sequencing, Genetics, MESH: Aged, MESH: Exome, MESH: Middle Aged, medicine.diagnostic_test, MESH: Retina, MESH: Genetic Predisposition to Disease, [SDV] Life Sciences [q-bio], MESH: Proteoglycans, MESH: Mutation, Sequence analysis, MESH: Pedigree, MESH: Arthrogryposis, Vitelliform macular dystrophy, Biology, MESH: Phenotype, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, MESH: Whole Exome Sequencing, Retinitis pigmentosa, medicine, MESH: Macular Degeneration, MESH: Genes, Recessive, Genetic testing, MESH: Humans, Genetic heterogeneity, eye diseases, MESH: Retrospective Studies, medicine.disease, MESH: Male, ophthalmology, 030104 developmental biology, 030221 ophthalmology & optometry, MESH: Retinitis Pigmentosa, genetic, MESH: Inheritance Patterns, MESH: Female
Abstract

BackgroundInherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.MethodsExome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role.ResultsExome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.ConclusionThis study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.

Published
2021
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6. Management of nasopharyngeal teratomas associated with cleft palate

Author

P. Guerreschi, Hervé Benateau, C. Diakité, S. Dakpé, Alexis Veyssière, P. Galinier, Biotechnologie des tissus conjonctifs et cutanés / Biology of Connective and Cutaneous Tissues (BioConnecT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Département de chirurgie maxillofaciale et stomatologie [CHU d'Amiens-Picardie], CHU Amiens-Picardie, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), and Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]

Subjects
Male, Pediatrics, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Prenatal diagnosis, Velopalatin cleft, Acute respiratory distress, Ultrasonography, Prenatal, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, 10. No inequality, Pathological, Retrospective Studies, Respiratory Distress Syndrome, business.industry, Mortality rate, Infant, Newborn, Teratoma, Nasopharyngeal Neoplasms, Retrospective cohort study, 030206 dentistry, University hospital, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Cleft Palate, Respiratory distress at birth, Treatment Outcome, Otorhinolaryngology, 030220 oncology & carcinogenesis, Operative time, Female, Surgery, Teratomas, Oral Surgery, Tomography, X-Ray Computed, business
Abstract

International audience; Nasopharyngeal teratomas are rare tumours, responsible for a high birth mortality rate from acute respiratory distress. Palatine localization can lead to an embryopathogenic mechanical obstacle responsible for a cleft palate. The aim of this study was to update current knowledge concerning the management of this rare pathological association.We conducted a multicentre, retrospective study by case analysis. The inclusion criteria were patients of any age under care for a nasopharyngeal teratoma associated with a velopalatine cleft. The diagnosis of the teratoma was confirmed by histological analysis.Seven cases were included in the study: three cases from the University Hospital of Lille, one from the University Hospital of Caen, one from of the University Hospital of Toulouse, and two from of the University Hospital of Amiens. Approximately 30% of patients experienced acute respiratory distress at birth, necessitating oro- or nasotracheal intubation. The surgical excision was performed in the first 5 months of life for all patients and in a single operative time for 70%. There was no recurrence.Therapeutic management of nasopharyngeal teratomas associated with cleft palate at birth is multidisciplinary and is based on surgical excision. In the absence of other associated pathologies, the prognosis is favourable.

Published
2019
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7. Air pollution-derived PM2.5 impairs mitochondrial function in healthy and chronic obstructive pulmonary diseased human bronchial epithelial cells

Author

J.-M. Lo Guidice, Anne Loyens, Jerome Kluza, Esperanza Perdrix, Patrice Coddeville, Jules Sotty, Laurent Y. Alleman, Guillaume Garçon, Philippe Marchetti, Sébastien Anthérieu, Bérénice Leclercq, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Département Sciences de l'Atmosphère et Génie de l'Environnement (SAGE), École des Mines de Douai (Mines Douai EMD), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Génie Civil et Environnemental (GCE), Centre for Energy and Environment (CERI EE), Ecole nationale supérieure Mines-Télécom Lille Douai (IMT Lille Douai), and Centre for Materials and Processes (CERI MP)

Subjects
0301 basic medicine, Mitochondrial ROS, Chemistry, Health, Toxicology and Mutagenesis, Cell, General Medicine, Oxidative phosphorylation, respiratory system, 010501 environmental sciences, Toxicology, 01 natural sciences, Pollution, Cell biology, 03 medical and health sciences, Cytosol, 030104 developmental biology, medicine.anatomical_structure, Apoptosis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, medicine, Cytokine secretion, Signal transduction, ComputingMilieux_MISCELLANEOUS, Homeostasis, 0105 earth and related environmental sciences
Abstract

In order to clarify whether the mitochondrial dysfunction is closely related to the cell homeostasis maintenance after particulate matter (PM2.5) exposure, oxidative, inflammatory, apoptotic and mitochondrial endpoints were carefully studied in human bronchial epithelial BEAS-2B, normal human bronchial epithelial (NHBE) and chronic obstructive pulmonary disease (COPD)-diseased human bronchial epithelial (DHBE) cells acutely or repeatedly exposed to air pollution-derived PM2.5. Some modifications of the mitochondrial morphology were observed within all these cell models repeatedly exposed to the highest dose of PM2.5. Dose- and exposure-dependent oxidative damages were reported in BEAS-2B, NHBE and particularly COPD-DHBE cells acutely or repeatedly exposed to PM2.5. Nuclear factor erythroid 2-p45 related factor 2 (NRF2) gene expression and binding activity, together with the mRNA levels of some NRF2 target genes, were directly related to the number of exposures for the lowest PM2.5 dose (i.e., 2 μg/cm2), but, surprisingly, inversely related to the number of exposures for the highest dose (i.e., 10 μg/cm2). There were dose- and exposure-dependent increases of both nuclear factor kappa-B (NF-κB) binding activity and NF-κB target cytokine secretion in BEAS-2B, NHBE and particularly COPD-DHBE cells exposed to PM2.5. Mitochondrial ROS production, membrane potential depolarization, oxidative phosphorylation, and ATP production were significantly altered in all the cell models repeatedly exposed to the highest dose of PM2.5. Collectively, our results indicate a cytosolic ROS overproduction, inducing oxidative damage and activating oxygen sensitive NRF2 and NF-kB signaling pathways for all the cell models acutely or repeatedly exposed to PM2.5. However, one of the important highlight of our findings is that the prolonged and repeated exposure in BEAS-2B, NHBE and in particular sensible COPD-DHBE cells further caused an oxidative boost able to partially inactivate the NRF2 signaling pathway and to critically impair mitochondrial redox homeostasis, thereby producing a persistent mitochondrial dysfunction and a lowering cell energy supply.

Published
2018
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8. N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Author

Rémy Umoret, Jeffrey M. Sequeira, Edward V. Quadros, Jean-Louis Guéant, Jean-Michel Camadro, Valérie Rigau, Sylvain Lehmann, Carine Bossenmeyer-Pourié, Bernard Sablonnière, A. David Smith, Déborah Helle, Jean-Luc Daval, Racha Kerek, Rosa-Maria Guéant-Rodriguez, Vincent Deramecourt, Audrey Gabelle, Grégory Pourié, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Biologie-Pathologie, UF de Neurobiologie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), SUNY Downstate Medical Center, State University of New York (SUNY), IMPACT GEENAGE, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), University of Oxford [Oxford], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), and Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]

Subjects
0301 basic medicine, medicine.medical_specialty, Hyperhomocysteinemia, Aging, Homocysteine, Normal diet, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, tau Proteins, folate, Pathology and Forensic Medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, Internal medicine, medicine, Animals, Humans, Cognitive Dysfunction, Vitamin B12, tau, Cognitive decline, Vascular dementia, Mice, Knockout, Alzheimer-type dementia, business.industry, Dementia, Vascular, microtubule-associated proteins, Brain, homocysteine, vitamin B12, medicine.disease, 3. Good health, Rats, 030104 developmental biology, Endocrinology, chemistry, Ageing, 030220 oncology & carcinogenesis, Female, Autopsy, business
Abstract

International audience; The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule-associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19-7 neuroprogenitors lacking folate. Compared with controls, N-homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N-homocysteinylation dissociated tau and MAPs from β-tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β-tubulin. N-homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days-old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy-thiolactone, the substrate of N-homocysteinylation. Experimental inactivation of MARS prevented the N-homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β-tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N-homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Published
2018
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9. Unlike ASXL1 and ASXL2 mutations, ASXL3 mutations are rare events in acute myeloid leukemia with t(8;21)

Author

Maxime Bucci, Hélène Lapillonne, Arnaud Petit, Nicolas Duployez, Sandrine Geffroy, Nicolas Boissel, Hervé Dombret, Norbert Ifrah, Aline Renneville, Eric Jourdan, Omar Abdel-Wahab, Claude Preudhomme, Guy Leverger, Jean-Baptiste Micol, Bernardo, Elizabeth, Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Human Oncology and Pathogenesis Program and Leukemia Service [New York, NY, USA], Memorial Sloane Kettering Cancer Center [New York]-Weill Medical College of Cornell University [New York], Hématologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'Hématologie Clinique [CHU d'Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département d'hématologie et d'oncologie [CHU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM), and Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]

Subjects
0301 basic medicine, Cancer Research, animal structures, Myeloid, Chromosomes, Human, Pair 21, Chromosomal translocation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, Translocation, Genetic, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Gene expression, medicine, Humans, Epigenetics, Gene, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, fungi, Myeloid leukemia, Hematology, medicine.disease, Repressor Proteins, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Oncology, Chromosomes, Human, Pair 8, Transcription Factors
Abstract

Additional sex combs-like (ASXL) genes are human homologues of the Drosophila-Asx gene encoding proteins that control gene expression through the regulation and the recruitment of epigenetic regula...

Published
2016
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10. Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French Acute Myeloid Leukemia Intergroup trial

Author

Hervé Dombret, Stephane Girault, Odile Blanchet, Romain Guieze, Céline Berthon, Christian Recher, Stéphane Leprêtre, Patrice Chevallier, Caroline Bonmati, Chantal Himberlin, Claude Preudhomme, Edouard Randriamalala, Cécile Pautas, Thomas Prebet, Eric Jourdan, Aline Renneville, Nicolas Boissel, Norbert Ifrah, Thibaut Leguay, Pascale Cornillet Lefebvre, Eric Delabesse, Thibaud Lecerf, Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Hématologie [CHRU Lille] (Centre de Biologie et de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Service d’Hématologie [Hôpital Haut-Lévèque, CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU de Bordeaux], Laboratoire Central d'Hématologie [Hôpital Robert Debré, CHU Reims], Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital universitaire Robert Debré [Reims], Service d'Hématologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des maladies du sang [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire d'Hématologie [Purpan], Service des Maladies du Sang [CHU Lille] (SMS), Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Hématologie [CHU Angers], Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d’Hématologie Adulte [Hôpitaux de Brabois, CHU Nancy], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Service d’Hématologie [Hôpital Robert Debré, CHU Reims], Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Hématologie Clinique et Oncologie Médicale [CHU de Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), The authors would like to thank Bristol-Myers Squibb and the Association Laurette Fugain for their financial support., Service d’Hématologie [CHU Purpan, Toulouse], Centre Hospitalier Universitaire de Purpan (CHU Purpan), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Service des Maladies du Sang [CHRU Lille], Bernardo, Elizabeth, Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Myeloid, Population, Dasatinib, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cohort Studies, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Maintenance therapy, Risk Factors, Internal medicine, hemic and lymphatic diseases, Humans, Medicine, education, Core binding factor acute myeloid leukemia, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, Core Binding Factors, Remission Induction, Myeloid leukemia, Articles, Hematology, Middle Aged, medicine.disease, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, RUNX1, chemistry, 030220 oncology & carcinogenesis, Immunology, Female, France, business, Follow-Up Studies, medicine.drug
Abstract

International audience; Core-binding factor acute myeloid leukemia is a favorable acute myeloid leukemia subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, disrupting RUNX1 (previously CBFA/AML1) or CBFB transcription factor functions. The receptor tyrosine kinase KIT is expressed in the vast majority of these acute myeloid leukemias and frequent activating KIT gene mutations have been associated with a higher risk of relapse. This phase II study aimed to evaluate dasatinib as maintenance therapy in patients with core-binding factor acute myeloid leukemia in first hematologic complete remission, but at higher risk of relapse due to molecular disease persistence or recurrence. A total of 26 patients aged 18-60 years old previously included in the CBF-2006 trial were eligible to receive dasatinib 140 mg daily if they had a poor initial molecular response (n=18) or a molecular recurrence (n=8). The tolerance of dasatinib as maintenance therapy was satisfactory. The 2-year disease-free survival in this high-risk population of patients was 25.7%. All but one patient with molecular recurrence presented subsequent hematologic relapse. Patients with slow initial molecular response had a similar disease-free survival when treated with dasatinib (40.2% at 2 years) or without any maintenance (50.0% at 2 years). The disappearance of KIT gene mutations at relapse suggests that clonal devolution may in part explain the absence of efficacy observed with single-agent dasatinib in these patients (n. EudraCT: 2006-006555-12).

Published
2015
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