Author: "Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris"' showing total 153 results

Start Over Author "Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris"

153 results on '"Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris"'

1. A polygenic risk score for multiple myeloma risk prediction

Author: Angelica Macauda, Matteo Pelosini, Krzysztof Jamroziak, Mario Petrini, Annette Juul Vangsted, Chiara Piredda, Stephane Minvielle, Marek Dudziński, Hervé Avet-Loiseau, Aleksandra Butrym, Ulla Vogel, Niels Abildgaard, Fabienne Lesueur, Waldemar Tomczak, Vibeke Andersen, Herlander Marques, Daniele Campa, Judit Várkonyi, Rui Manuel Reis, Katalin Kadar, Gabriele Buda, Małgorzata Raźny, Charles Dumontet, Juan Sainz, Anna Suska, Enrico Orciuolo, Agnieszka Druzd-Sitek, Marcin Kruszewski, Daria Zawirska, Niels Frost Andersen, Artur Jurczyszyn, Grzegorz Mazur, Marcin Rymko, Federica Gemignani, Edyta Subocz, Federico Canzian, Katia Beider, Jan Maciej Zaucha, Marzena Wątek, Arnon Nagler, Genomic Epidemiology Group [Heidelberg, Germany] (GEP / DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Pisa - Università di Pisa, University Hospital of Cracow/Szpital Uniwersytecki w Krakowie [Poland] (SUK), Aarhus University Hospital, Chaim Sheba Medical Center, Sea Hospital [Gdynia, Poland] (SH), Wroclaw Medical University [Wrocław, Pologne] (WMU), Hospices Civils de Lyon (HCL), Holycross Cancer Center of Kelce, Hematology Clinic, Kielce, Institute of Hematology and Transfusion Medicine [Warsaw, Poland] (IHTM), Centre for Genomics and Oncological Research Pfizer [Granada, Spain] (GENYO), University of Granada [Granada]-Andalusian Regional Government [Granada, Spain], Hospital Universitario Virgen de las Nieves [Granada, Spain] (HUVN), Semmelweis University [Budapest], Odense University Hospital (OUH), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Teaching Hospital No 1 [Rzeszów, Poland] (TH1), University of Copenhagen = Københavns Universitet (KU), Military Institute of Medicine [Warsaw, Poland] (MIM), Rydygier Specialistic Hospital [Cracow, Poland] (RSH), University of Minho [Braga], Jagiellonian University Medical College [Cracow, Poland] (JUMC), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), The National Research Center for Work Environment [Copenhagen, Denmark] (NRCWE), University of Southern Denmark (SDU), ICVS/3B's - PT Government Associate Laboratory [Braga/Guimarães, Portugal] (AL), Barretos Cancer Hospital [São Paulo, Brazil] (BCH), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Bydgoszcz [Bydgoszcz, Poland] (UHB), Medical University of Lublin, N. Copernicus Town Hospital [Torun, Poland] (NCTH), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), 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), Bernardo, Elizabeth, Wrocław Medical University, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government [Granada, Spain], Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), 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), and 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)
Subjects: Oncology, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, education, Genetics (clinical), Multiple myeloma, 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, business.industry, medicine.disease, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Polygenic risk score, Multiple Myeloma, business, Genome-Wide Association Study
Abstract: This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis., There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., University of Pisa, DKFZ, University Hospital of Southern Jutland, Denmark, Institut National du Cancer (INCA) France
Published: 2021

2. Identification de régulateurs systémiques de l'horloge périphérique circadienne par apprentissage de modèles

Author: Sylvain Soliman, Annabelle Ballesta, François Fages, Xiao-Mei Li, Julien Martinelli, Michèle Teboul, Sandrine Dulong, Francis Lévi, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Computational systems biology and optimization (Lifeware), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Paris-Saclay, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and MINES ParisTech - École nationale supérieure des mines de Paris
Subjects: 0301 basic medicine, Statistics and Probability, AcademicSubjects/SCI01060, Systems biology, medicine.medical_treatment, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], Population, Circadian clock, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Bioinformatics, Biochemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Circadian Clocks, Machine learning, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Animals, Humans, Circadian rhythm, education, Molecular Biology, education.field_of_study, business.industry, Precision medicine, Chronotherapy (treatment scheduling), Circadian Rhythm, 3. Good health, Computer Science Applications, PER2, Computational Mathematics, 030104 developmental biology, Gene Expression Regulation, Computational Theory and Mathematics, Systems Biology and Networks, Personalized medicine, Network Inference, business, 030217 neurology & neurosurgery
Abstract: Motivation Personalized medicine aims at providing patient-tailored therapeutics based on multi-type data toward improved treatment outcomes. Chronotherapy that consists in adapting drug administration to the patient’s circadian rhythms may be improved by such approach. Recent clinical studies demonstrated large variability in patients’ circadian coordination and optimal drug timing. Consequently, new eHealth platforms allow the monitoring of circadian biomarkers in individual patients through wearable technologies (rest-activity, body temperature), blood or salivary samples (melatonin, cortisol) and daily questionnaires (food intake, symptoms). A current clinical challenge involves designing a methodology predicting from circadian biomarkers the patient peripheral circadian clocks and associated optimal drug timing. The mammalian circadian timing system being largely conserved between mouse and humans yet with phase opposition, the study was developed using available mouse datasets. Results We investigated at the molecular scale the influence of systemic regulators (e.g. temperature, hormones) on peripheral clocks, through a model learning approach involving systems biology models based on ordinary differential equations. Using as prior knowledge our existing circadian clock model, we derived an approximation for the action of systemic regulators on the expression of three core-clock genes: Bmal1, Per2 and Rev-Erbα. These time profiles were then fitted with a population of models, based on linear regression. Best models involved a modulation of either Bmal1 or Per2 transcription most likely by temperature or nutrient exposure cycles. This agreed with biological knowledge on temperature-dependent control of Per2 transcription. The strengths of systemic regulations were found to be significantly different according to mouse sex and genetic background. Availability and implementation https://gitlab.inria.fr/julmarti/model-learning-mb21eccb. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2021

3. Parental-to-embryo switch of chromosome organization in early embryogenesis

Author: Wing Leung, Samuel Collombet, Maud Borensztein, Tarak Shisode, Katia Ancelin, Csilla Várnai, Tristan Piolot, Nicolas Servant, Edith Heard, Rafael Galupa, Takashi Nagano, Peter Fraser, Noémie Ranisavljevic, European Molecular Biology Laboratory [Heidelberg] (EMBL), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], and Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Parents, Embryonic Development, Polycomb-Group Proteins, Biology, Methylation, Histones, Chromosome conformation capture, Genomic Imprinting, Mice, 03 medical and health sciences, Histone H3, 0302 clinical medicine, X Chromosome Inactivation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Medicine, Chromosome Positioning, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Gene, Alleles, ComputingMilieux_MISCELLANEOUS, Genomic organization, 030304 developmental biology, Epigenomics, Genetics, Regulation of gene expression, 0303 health sciences, Genome, Multidisciplinary, business.industry, Gene Expression Regulation, Developmental, Obstetrics and Gynecology, General Medicine, Chromosomes, Mammalian, Chromatin, Blastocyst, Germ Cells, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Histone, Fertilization, biology.protein, Female, Single-Cell Analysis, business, Genomic imprinting, 030217 neurology & neurosurgery
Abstract: Paternal and maternal epigenomes undergo marked changes after fertilization1. Recent epigenomic studies have revealed the unusual chromatin landscapes that are present in oocytes, sperm and early preimplantation embryos, including atypical patterns of histone modifications2–4 and differences in chromosome organization and accessibility, both in gametes5–8 and after fertilization5,8–10. However, these studies have led to very different conclusions: the global absence of local topological-associated domains (TADs) in gametes and their appearance in the embryo8,9 versus the pre-existence of TADs and loops in the zygote5,11. The questions of whether parental structures can be inherited in the newly formed embryo and how these structures might relate to allele-specific gene regulation remain open. Here we map genomic interactions for each parental genome (including the X chromosome), using an optimized single-cell high-throughput chromosome conformation capture (HiC) protocol12,13, during preimplantation in the mouse. We integrate chromosome organization with allelic expression states and chromatin marks, and reveal that higher-order chromatin structure after fertilization coincides with an allele-specific enrichment of methylation of histone H3 at lysine 27. These early parental-specific domains correlate with gene repression and participate in parentally biased gene expression—including in recently described, transiently imprinted loci14. We also find TADs that arise in a non-parental-specific manner during a second wave of genome assembly. These de novo domains are associated with active chromatin. Finally, we obtain insights into the relationship between TADs and gene expression by investigating structural changes to the paternal X chromosome before and during X chromosome inactivation in preimplantation female embryos15. We find that TADs are lost as genes become silenced on the paternal X chromosome but linger in regions that escape X chromosome inactivation. These findings demonstrate the complex dynamics of three-dimensional genome organization and gene expression during early development. Single-cell allelic HiC analysis, combined with allelic gene expression and chromatin states, reveals parent-of-origin-specific dynamics of chromosome organization and gene expression during mouse preimplantation development.
Published: 2020

4. A review of the use of time‐varying covariates in the Fine‐Gray subdistribution hazard competing risk regression model

Author: Peter C. Austin, Aurélien Latouche, Jason P. Fine, University of Toronto, Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, CEDRIC. Méthodes statistiques de data-mining et apprentissage (CEDRIC - MSDMA), Centre d'études et de recherche en informatique et communications (CEDRIC), Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of North Carolina [Chapel Hill] (UNC), and University of North Carolina System (UNC)
Subjects: Statistics and Probability, Time-varying covariate, Epidemiology, Competing risks, 01 natural sciences, survival analysis, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Covariate, Econometrics, Medicine, 030212 general & internal medicine, time-varying covariate, 0101 mathematics, Survival analysis, Research Articles, time‐varying covariate, competing risks, [STAT.AP]Statistics [stat]/Applications [stat.AP], Proportional hazards model, business.industry, Regression analysis, 3. Good health, Survival function, Subdistribution hazard, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, subdistribution hazard model, business, Research Article
Abstract: International audience; In survival analysis, time-varying covariates are covariates whose value can change during follow-up. Outcomes in medical research are frequently subject to competing risks (events precluding the occurrence of the primary outcome). We review the types of time-varying covariates and highlight the effect of their inclusion in the subdistribution hazard model. External time-dependent covariates are external to the subject, can effect the failure process, but are not otherwise involved in the failure mechanism. Internal time-varying covariates are measured on the subject, can effect the failure process directly, and may also be impacted by the failure mechanism. In the absence of competing risks, a consequence of including internal time-dependent covariates in the Cox model is that one cannot estimate the survival function or the effect of covariates on the survival function. In the presence of competing risks, the inclusion of internal time-varying covariates in a subdistribution hazard model results in the loss of the ability to estimate the cumulative incidence function (CIF) or the effect of covariates on the CIF. Furthermore, the definition of the risk set for the subdistribution hazard function can make defining internal time-varying covari-ates difficult or impossible. We conducted a review of the use of time-varying covariates in subdistribution hazard models in articles published in the medical literature in 2015 and in the first 5 months of 2019. Seven percent of articles published included a time-varying covariate. Several inappropriately described a time-varying covariate as having an association with the risk of the outcome.
Published: 2019

5. Evaluation of least significant changes of pulse contour analysis-derived parameters

Author: Eric Verchère, Matthieu Biais, Gregoire Cane, Hugues de Courson, Karine Nouette-Gaulain, Musa Sesay, Loic Ferrer, Service Anesthésie - Réanimation [Bordeaux], CHU Bordeaux [Bordeaux], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), This study was supported from institutional and departmental sources., Boullé, Christelle, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Fluid responsiveness, Cardiac index, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030202 anesthesiology, Contour analysis, Internal medicine, Occlusion, Article CLINIQUE, Medicine, Pulse (signal processing), business.industry, Research, Pulse pressure variation, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, Stroke volume, lcsh:RC86-88.9, Precision, Pulse pressure, Lung recruitment, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Stroke volume variation, Cardiology, business, Pulse contour
Abstract: Background Many maneuvers assessing fluid responsiveness (minifluid challenge, lung recruitment maneuver, end-expiratory occlusion test, passive leg raising) are considered as positive when small variations in cardiac index, stroke volume index, stroke volume variation or pulse pressure variation occur. Pulse contour analysis allows continuous and real-time cardiac index, stroke volume, stroke volume variation and pulse pressure variation estimations. To use these maneuvers with pulse contour analysis, the knowledge of the minimal change that needs to be measured by a device to recognize a real change (least significant change) has to be studied. The aim of this study was to evaluate the least significant change of cardiac index, stroke volume index, stroke volume variation and pulse pressure variation obtained using pulse contour analysis (ProAQT®, Pulsion Medical System, Germany). Methods In this observational study, we included 50 mechanically ventilated patients undergoing neurosurgery in the operating room. Cardiac index, stroke volume index, pulse pressure variation and stroke volume variation obtained using ProAQT® (Pulsion Medical System, Germany) were recorded every 12 s during 15-min steady-state periods. Least significant changes were calculated every minute. Results Least significant changes statistically differed over time for cardiac index, stroke volume index, pulse pressure variation and stroke volume variation (p Conclusion To conclude, the present study suggests that pulse contour analysis is able to detect rapid and small changes in cardiac index and stroke volume index, but the interpretation of rapid and small changes of pulse pressure variation and stroke volume variation must be done with caution.
Published: 2019

6. Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation

Author: Michel Longy, Christine Maugard, Elisabeth Luporsi, Capucine Delnatte, Séverine Eon-Marchais, Marion Gauthier-Villars, Juana Beauvallet, Noura Mebirouk, Muriel Belotti, Alain Lortholary, Sophie Lejeune-Dumoulin, Christine Lasset, Isabelle Mortemousque, Yves-Jean Bignon, François Eisinger, Sylvie Mazoyer, Valérie Bonadona, Jean-Marc Limacher, Anne Tardivon, Paul Gesta, Sandra Fert-Ferrer, Fabienne Lesueur, Dorothée Le Gal, Jean Chiesa, Florent Soubrier, Pascaline Berthet, Laurence Faivre, Bruno Buecher, Nadine Andrieu, Juliette Coignard, Julie Tinat, Thierry Frebourg, Isabelle Coupier, Sophie Giraud, Laure Barjhoux, Catherine Noguès, Séverine Audebert-Bellanger, Claude Adenis-Lavignasse, Chrystelle Colas, Maximiliano Ribeiro Guerra, Laurence Venat-Bouvet, Eve Cavaciuti, Anne Floquet, Pascal Pujol, Francesca Damiola, Anne Fajac, Jean-Pierre Fricker, Hélène Dreyfus, Dominique Stoppa-Lyonnet, Marie-Gabrielle Dondon, Laurence Gladieff, Olivier Caron, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Federal University of Juiz de Fora (UFIJ), Institut Gustave Roussy (IGR), AP-HP. Université Paris Saclay, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Catherine-de-Sienne [Nantes] (CCS), Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Hôpital de Mercy, Centre René Gauducheau, CRLCC René Gauducheau, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Bergonié [Bordeaux], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Ramsay Générale de Santé - Hôpital Privé La Louvière, Hôpital Dupuytren [CHU Limoges], Institut Sainte Catherine [Avignon], hôpital couple-enfant [CHU Grenoble Alpes], Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), 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), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Morvan [Brest], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Groupement Hospitalier Lyon-Est (GHE), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital pasteur [Colmar], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Métropole Savoie [Chambéry], Hôpital René HUGUENIN (Saint-Cloud), CHU Rouen, Normandie Université (NU), Hôpital Edouard Herriot [CHU - HCL], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), MINES ParisTech - École nationale supérieure des mines de Paris, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), COLO, Mouniati, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Risk, Oncology, medicine.medical_specialty, DNA Repair, DNA repair, [SDV]Life Sciences [q-bio], Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, X-ray exposure, Logistic regression, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Surgical oncology, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, RC254-282, High-risk population, Pregnancy, DNA repair genes, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Middle Aged, medicine.disease, 3. Good health, Radiography, [SDV] Life Sciences [q-bio], Low dose, 030220 oncology & carcinogenesis, Mutation, Female, business, Research Article
Abstract: Background Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. Methods We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. Results Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. Conclusion Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.
Published: 2021

7. The kinesin KIF1C transports APC-dependent mRNAs to cell protrusions

Author: Emeline Coleno, Marion Peter, Marie-Cécile Robert, Tianhong Wang, Xavier Pichon, Kazem Zibara, Arthur Imbert, Edouard Bertrand, Florian Mueller, Thomas Walter, Stavroula Mili, Racha Chouaib, Konstadinos Moissoglu, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'économie et de sociologie du travail (LEST), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Equipe labellisée Ligue contre le Cancer, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institut de génétique humaine (IGH), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lebanese University [Beirut] (LU), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), This project was supported by France BioImaging (ANR-10-INBS-04), the Agence Nationale de la Recherche (ANR-11-BSV8-018-02, ANR-14-CE10-0018-01 and ANR-19-CE12-0007-03), and the Ligue Nationale Contre le Cancer and the Fondation pour la Recherche Médicale. This work was supported by the Labex EpiGenMed, from the framework 'Investissements d’avenir'. This work was supported in part by the Intramural Research Program of the National Cancer Institute, NIH., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-11-BSV8-0018,EJCbirth,Impacts de la transcription par l'ARN polymérase II sur l'assemblage de l'EJC(2011), ANR-14-CE10-0018,HI-FISH,Etude systématique de l'expression des gènes à l'échelle des molécules uniques d'ARN(2014), ANR-19-CE12-0007,TRANSFACT,Caracterisation des foyers de traduction: de nouvelles structures qui organisement finement le cytoplasme(2019), ANR-10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cytoplasm, RNA localization, [SDV]Life Sciences [q-bio], Adenomatous Polyposis Coli Protein, RNA transport, Kinesins, Biology, Article, RNA Transport, 03 medical and health sciences, local translation, 0302 clinical medicine, Live cell imaging, MRNA transport, Animals, Humans, RNA, Messenger, Molecular Biology, cytoplasmic protrusions, 030304 developmental biology, 0303 health sciences, Messenger RNA, RNA, Cell biology, Kinesin, Cell Surface Extensions, 030217 neurology & neurosurgery, HeLa Cells
Abstract: International audience; RNA localization and local translation are important for numerous cellular functions. In mammals, a class of mRNAs localize to cytoplasmic protrusions in an APC-dependent manner, with roles during cell migration. Here, we investigated this localization mechanism. We found that the KIF1C motor interacts with APC-dependent mRNAs and is required for their localization. Live cell imaging revealed rapid, active transport of single mRNAs over long distances that requires both microtubules and KIF1C. Two color imaging directly revealed single mRNAs transported by single KIF1C motors, with the 3’UTR being sufficient to trigger KIF1C-dependent RNA transport and localization. Moreover, KIF1C remained associated with peripheral, multimeric RNA clusters and was required for their formation. These results reveal a widespread RNA transport pathway in mammalian cells, in which the KIF1C motor has a dual role in transporting RNAs and clustering them within cytoplasmic protrusions. Interestingly, KIF1C also transports its own mRNA suggesting a possible feedback loop acting at the level of mRNA transport.
Published: 2021

8. Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma

Author: Franck Letourneur, Jérémy Augustin, Mark J. Kurth, Julie Le Naour, Sylvie Lachkar, Pamela Caudana, Eliane Piaggio, Youra Kim, Sarah Levesque, Jie S. Zhu, Guido Kroemer, Jonathan Pol, Bouchra Lekbaby, Andrea Checcoli, Patrick S.C. Leung, Allan Sauvat, Shashi Gujar, Agathe Delaune, Chantal Housset, Pierre de la Grange, Paule Opolon, Laura Fouassier, Noémie Robil, Laurence Zitvogel, Patrick Soussan, Juliette Paillet, Céleste Plantureux, Jimena Tosello Boari, M. Eric Gershwin, Isabelle Martins, Maria Chiara Maiuri, Cédric Coulouarn, Gautier Stoll, Norma Bloy, Gwennhael Autret, Juliette Hamroune, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Gustave Roussy (IGR), Institut Curie [Paris], Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), GenoSplice [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of California [Los Angeles] (UCLA), University of California, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dalhousie University [Halifax], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska University Hospital [Stockholm], Association pour la lutte contre les maladies inflammatoires du foie et des voies biliaires, Dalhousie Medical Research Foundation, Agence National de la Recherche, ERA-Net for Research on Rare Diseases, Association pour la recherche sur le cancer, Cancéropôle Ile-de-France, Chancellerie des universités de Paris, Fondation pour la Recherche Médicale, Elior, European Research Area Network on Cardiovascular Diseases, Gustave Roussy Odyssea, European Union Horizon 2020, Canadian Cancer Society, Project Oncobiome, Fondation Carrefour, GDW20171100085, High-end Foreign Expert Program in China, Institut National du Cancer, Inserm, Institut Universitaire de France, LeDucq Foundation, LabEx, Recherche Hospitalo-Universitaire Torino Lumière, Seerave Foundation, Canadian Institutes of Health Research, Site de Recherche intégrée sur le Cancer Stratified Oncology Cell DNA Repair and Tumor Immune Elimination, Cancer Research and Personalized Medicine, Multi-Organism Institute (ITMO) Aviesan Cancer, Association Française d'Hépatologie, Site de Recherche intégrée sur le Cancer Cancer Research and Personalized Medicine, Ligue contre le Cancer, École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California (UC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: CD4-Positive T-Lymphocytes, Cholangitis, Autoimmunity, CD8-Positive T-Lymphocytes, Inbred C57BL, medicine.disease_cause, Medical and Health Sciences, Malignant transformation, Cholangiocarcinoma, Mice, 0302 clinical medicine, Immunologic, Neoplasms, 2.1 Biological and endogenous factors, Immunology and Allergy, Medicine, Aetiology, Cancer, 0303 health sciences, Tumor, Liver Disease, Forkhead Transcription Factors, 3. Good health, Immunosurveillance, medicine.anatomical_structure, Liver, Biliary tract, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, cardiovascular system, Cytokines, Female, Biotechnology, Liver Cancer, Monitoring, T cell, Chronic Liver Disease and Cirrhosis, Immunology, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Autoimmune Disease, digestive system, Cell Line, Primary sclerosing cholangitis, Experimental, 03 medical and health sciences, Rare Diseases, Monitoring, Immunologic, Cell Line, Tumor, parasitic diseases, Animals, cardiovascular diseases, Digestive Diseases - (Gallbladder), 030304 developmental biology, business.industry, Neoplasms, Experimental, medicine.disease, digestive system diseases, Mice, Inbred C57BL, Bile Duct Neoplasms, Cancer research, Digestive Diseases, business
Abstract: International audience; Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.
Published: 2021

9. Spatial transcriptomics for respiratory research and medicine

Author: Arturo Londoño-Vallejo, Juliette Soulier, Thomas Walter, Florian Mueller, Sandra Curras-Alonso, Charles Fouillade, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et Modélisation - Imaging and Modeling, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), We acknowledge financial support from Agence National de la Recherche (ANR-14-CE36-0008-02 program), the Comprehensive Cancer Center 'SIRIC' program of Institut Curie (Grant INCa-DGOS-4654) as well as the grants ANR-10-EQPX-03 (Equipex), ANR-10-INBS-09-08 (France Génomique Consortium) from the Agence Nationale de la Recherche (Investissements d'Avenir program) for the NGS core facility of Institut Curie., ANR-14-CE36-0008,FLASH-RT,FLASH, a novel radiotherapy modality Understanding physical interaction and biological effect of FLASH radiotherapy on haematopoiesis and leukaemia(2014), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pulmonary and Respiratory Medicine, Lung, business.industry, Gene Expression Profiling, Computational biology, Respiratory physiology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, respiratory system, Cellular level, respiratory tract diseases, 3. Good health, Transcriptome, medicine.anatomical_structure, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Single-Cell Analysis, Respiratory system, business, ComputingMilieux_MISCELLANEOUS
Abstract: In combination with scRNA-seq, spatial transcriptomics have the potential to lead to an unprecedented view of lung architecture at the single cell level, providing original information on lung physiology and physiopathologyhttps://bit.ly/3uDYir0
Published: 2021

10. FISH-quant v2: a scalable and modular analysis tool for smFISH image analysis

Author: Edouard Bertrand, Christophe Zimmer, Thomas Walter, Arthur Imbert, Adham Safieddine, Wei Ouyang, Emeline Coleno, Florian Mueller, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Royal Institute of Technology [Stockholm] (KTH ), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ANR-19-CE12-0007,TRANSFACT,Caracterisation des foyers de traduction: de nouvelles structures qui organisement finement le cytoplasme(2019), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), MINES ParisTech - École nationale supérieure des mines de Paris, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie mitochondriale – Mitochondrial biology, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)
Subjects: Messenger RNA, RNA localization, business.industry, Computer science, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], RNA, Computational biology, Modular design, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Image (mathematics), [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Scalability, Gene expression, %22">Fish , [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business
Abstract: Regulation of RNA abundance and localization is a key step in gene expression control. Single-molecule RNA fluorescence in-situ hybridization (smFISH) is a widely used single-cell-single-molecule imaging technique enabling a quantitative understanding of gene expression and its regulatory mechanisms. Recent progress in experimental techniques provides larger data-sets, requiring adequate tools for data analysis and exploration. Here, we present FISH-quant v2, a highly modular analysis tool accessible both for non-experts and experts, which we validated and applied on large-scale smFISH image datasets. Our package allows the user to detect isolated and clustered mRNA spots, segment nuclei and cells, quantify RNA localization patterns and visualize these results at the single-cell level.
Published: 2021

11. TUMOSPEC: A Nation-Wide Study of Hereditary Breast and Ovarian Cancer Families with a Predicted Pathogenic Variant Identified through Multigene Panel Testing

Author: Celine Garrec, Monique Mozelle-Nivoix, Jérôme Lemonnier, Etienne Rouleau, Tan Dat Nguyen, Dominique Vaur, Elodie Lacaze, Sarah Bonnet-Boissinot, Sophie Nambot, Jean Chiesa, Sophie Giraud, Dominique Stoppa-Lyonnet, Michel Longy, Alain Lortholary, Jean-Marc Rey, Olivier Caron, Christine Lasset, Claude Houdayer, Christine Maugard, Virginie Bubien, Véronique Mari, Marie-Emmanuelle Morin-Meschin, Nadine Andrieu, Nancy Uhrhammer, Louise Crivelli, Hélène Dreyfus, Vincent Goussot, Stephanie Chieze-Valéro, Nicolas Sevenet, Lisa Golmard, Séverine Eon-Marchais, Mathilde Martinez, Isabelle Coupier, Marie-Gabrielle Dondon, Odile Béra, Paul Vilquin, Capucine Delnatte, Odile Cohen-Haguenauer, Cornel Popovici, Christine Toulas, Laurence Gladieff, Marie-Agnès Collonge-Rame, Chrystelle Colas, Paul Gesta, Catherine Noguès, Fanny Brayotel, Audrey Mailliez, Fabienne Lesueur, Julie Tinat, Marie Bidart, Yves-Jean Bignon, Florence Coulet, Nadia Boutry-Kryza, Fabienne Prieur, Juana Beauvallet, Philippe Denizeau, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôtel-Dieu de Nantes, CHU Rouen, Normandie Université (NU), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jean Godinot [Reims], UNICANCER, Centre Eugène Marquis (CRLCC), Institut de Cancérologie de Strasbourg Europe (ICANS), Centre Paul Strauss, CRLCC Paul Strauss, Institut Bergonié [Bordeaux], Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Genetic and Immunology Medical Institute (GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CHU de Saint-Étienne Hôpital Nord [Saint Etienne], Hôpital Nord (Saint Etienne), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), CHU Bordeaux [Bordeaux], Centre Catherine-de-Sienne [Nantes] (CCS), Hôpital privé du Confluent [Nantes], Institut Sainte Catherine [Avignon], hôpital couple-enfant [CHU Grenoble Alpes], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier de Troyes, Hospices Civils de Lyon (HCL), Groupement Hospitalier Lyon-Est (GHE), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe Hospitalier du Havre, CHU de la Martinique [Fort de France], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CRLCC René Gauducheau, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre médical de Bligny, Onco-génétique, Département de médecine oncologique [Gustave Roussy], COLO, Mouniati, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Lille-UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), 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), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, Sequencing data, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030105 genetics & heredity, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Care plan, Internal medicine, Epidemiology, medicine, RC254-282, Genetic testing, medicine.diagnostic_test, business.industry, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, genetic predisposition to breast and ovarian cancer, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Oncology, 030220 oncology & carcinogenesis, multigene panels, Cancer risk, Ovarian cancer, business, cancer risk estimate, penetrance of pathogenic variants
Abstract: Simple Summary TUMOSPEC was designed for estimating the risk of cancer for carriers of a predicted pathogenic variant (PPV) in a gene usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and are tested for the familial PPV. Genetic, clinical, family and epidemiological data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. This showed that the study logistics are well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) is smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene. Abstract Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and genotyped for the familial PPV. Clinical, family and epidemiological data are collected, and all data including sequencing data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. When invited by the coordinating centre, 65.3% of the relatives of index cases (5.7 relatives per family, on average) accepted the invitation to participate. The study logistics were well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) was smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene.
Published: 2021

12. Role of DNA Repair Variants and Diagnostic Radiology Exams in Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case–Control Studies

Author: Carole Rubino, Pascal Guénel, Emilie Cordina-Duverger, Françoise Borson-Chazot, Vincent Souchard, Pierre Laurent-Puig, Florent de Vathaire, Thérèse Truong, Julie Guibon, Anne-Valérie Guizard, Mojgan Karimi, Elizabeth Adjadj, Catherine Ory, Hélène Blanché, Jean-Baptiste Cazier, Sylvie Chevillard, Martin Schlumberger, Constance Xhaard, Claire Schvartz, Yan Ren, Fabienne Lesueur, Jean-François Deleuze, Anne Boland, Mohammed Zakarya Zemmache, Sandra Canale, Eugènia Mariné Barjoan, Claire Mulot, Monia Zidane, Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Université Paris-Saclay, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), Laboratory of Excellence GENMED (Medical Genomics), Laboratoire de Cancérologie Expérimentale (LCE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Service de Radobiologie Expérimentale et Innovation Technologique (SREIT), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Godinot [Reims], UNICANCER, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Epigenetec, Centre de Ressources Biologiques (CRB), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), University of Birmingham [Birmingham], FDV received the following grants as principal investigator of Young-Thyr study: Fondation de France (Grant number 65391), L'Alliance pour les sciences de la vie et de la santé, « AVIESAN » (Grants number ENV201416 and 2007005070), the Ligue Nationale Contre le Cancer (LNCC) (Grants number EPDAC6036, EPDTP6004, R10127LL).TT received the following grants for CATHY 470 and Young-Thyr studies genotyping Institut National du Cancer (Grant number 9533), the ARC foundation (Grant number PGA120150202302) MZ performed this work during her PhD funded by Ecole des Hautes Etudes en Santé Publique (EHESP) and the ARC Foundation (Grant number ARCDOC42020070002532)., Université Paris Sud Orsay, Inserm, U900, Institut Curie, Université PSL, Mines ParisTech, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, and BOZEC, Erwan
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Neoplasms, Radiation-Induced, Adolescent, DNA Repair, Epidemiology, DNA repair, Thyroid Gland, Single-nucleotide polymorphism, Logistic regression, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Genetic predisposition, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Thyroid Neoplasms, Child, Thyroid cancer, Aged, Aged, 80 and over, business.industry, Thyroid, Case-control study, Dose-Response Relationship, Radiation, Middle Aged, medicine.disease, Confidence interval, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Radiology, France, business
Abstract: Background: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer. Methods: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case–control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies. Results: The OR/mGy was 1.02 (95% confidence interval, 1.00–1.03). We found significant associations between DTC and rs7164173 in CHD2 (P = 5.79 × 10−5), rs6067822 in NFATc2 (P = 9.26 × 10−5), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses (P = 3.40 × 10−4). Conclusions: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk. Impact: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.
Published: 2021

13. Has tumor doubling time in breast cancer changed over the past 80 years? A systematic review

Author: Delphine Hequet, Claire Bonneau, Xavier Paoletti, Meryl Dahan, Roman Rouzier, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), MD was supported by the Malakoff Mederic group., HAL UVSQ, Équipe, Mines Paris - PSL (École nationale supérieure des mines de Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Time Factors, Overdiagnosis, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Reviews, Breast Neoplasms, Triple Negative Breast Neoplasms, Review, 03 medical and health sciences, 0302 clinical medicine, Qualitative analysis, Breast cancer, breast cancer, Internal medicine, Medicine, Doubling time, Humans, Mass Screening, Radiology, Nuclear Medicine and imaging, Tumor growth, 030212 general & internal medicine, Prospective cohort study, RC254-282, Cell Proliferation, Cancer Biology, molecular subtypes, Tumor size, business.industry, screening, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, Tumor Burden, [SDV] Life Sciences [q-bio], Ki-67 Antigen, 030220 oncology & carcinogenesis, tumor growth rate, Regression Analysis, Female, Electronic database, tumor doubling time, business
Abstract: Over the past century, epidemiologic changes and implementation of screening may have had an impact on tumor doubling time in breast cancer. Our study was designed to evaluate changes in tumor doubling time in breast cancer over the past 80 years. A systematic review of published literature and meta‐regression analysis was performed. An online electronic database search was undertaken using the PubMed platform from inception until June 2020. All studies that measured tumor doubling time in breast cancer were included. A total of 151 publications were retrieved. Among them, 16 full‐text articles were included in the qualitative analysis. An exponential growth model was used for quantitative characterization of tumor growth rate. Tumor doubling time has remained stable over the past 80 years. Recent studies have not only identified “fast growing tumor” (grade 3, human epidermal growth factor receptor 2‐positive, triple‐negative, or tumor with an elevated Ki‐67) but also “inactive breast cancer” feeding the ongoing debate of overdiagnosis due to screening programs. The stability of tumor doubling time over the past 80 years, despite increasing and changing risk factors, supports the validity for our screening guidelines. Prospective studies based on more precise measurement of tumor size and adjustment for tumor characteristics are necessary to more clearly characterize the prognostic and predictive impact of tumor doubling time in breast cancer., The stability of tumor doubling time over the past 80 years, despite increasing and changing risk factors, supports the validity of our screening guidelines. Recent studies have not only identified “fast growing tumor” but also “inactive breast cancer” feeding the ongoing debate of overdiagnosis due to screening programs.
Published: 2021

14. The Phosphatase PRL-3 Is Involved in Key Steps of Cancer Metastasis

Author: Laura Duciel, S Saule, Maria Kondratova, Luis Cristobal Monraz Gomez, Inna Kuperstein, Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Subjects: endocrine system, Carcinogenesis, Angiogenesis, [SDV]Life Sciences [q-bio], Systems biology, Phosphatase, Apoptosis, Computational biology, Biology, medicine.disease_cause, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Structural Biology, Cell Line, Tumor, Cell Adhesion, medicine, Humans, Neoplasm Metastasis, Molecular Biology, Cytoskeleton, 030304 developmental biology, 0303 health sciences, Systems Biology, Cell Cycle, Cancer, Cell cycle, medicine.disease, Neoplasm Proteins, 3. Good health, Disease Progression, Protein Tyrosine Phosphatases, Signal transduction, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery, Signal Transduction
Abstract: PRL-3 belongs to the PRL phosphatase family. Its physiological role remains unclear, but many studies have identified that PRL-3 is a marker of cancer progression and shown it to be associated with metastasis. Evidence implicating PRL-3 in various elements of the metastatic process, such as the cell cycle, survival, angiogenesis, adhesion, cytoskeleton remodeling, EMT, motility and invasion, has been reported. Furthermore, several molecules acting as direct or indirect substrates have been identified. However, this information was obtained in many different studies, and it remains difficult to see the larger picture. We therefore systematically collected the published information together and used it to develop a comprehensive signaling network map. By analyzing this network map, we were able to retrieve the signaling pathways via which PRL-3 governs the key steps of the metastatic process in cancer. In this review, we summarize current knowledge of the role of PRL-3 in cancer and the molecular mechanisms involved. We also provide the web-based open-source PRL-3 signaling network map, for use in further studies.
Published: 2019

15. OSIRIS: A Minimum Data Set for Data Sharing and Interoperability in Oncology

Author: Vincent Le Texier, Laetitia Chanas, Pierre Saintigny, Sophie Gourgou, Vianney Jouhet, Marina Rousseau-Tsangaris, Manuel Tejeda, Bastien Rance, Julien Guerin, Anne-Laure Martin, Yec'han Laizet, Maud Toulmonde, Elisabeth Hess, François Lion, Florence Koeppel, Stéphanie Cox, Institut Curie [Paris], Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre Léon Bérard [Lyon], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut du Cancer de Montpellier (ICM), UNICANCER, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Bergonié [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Admin, Oskar
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Computer science, Genomic data, Interoperability, MEDLINE, Information Dissemination, [SDV.CAN]Life Sciences [q-bio]/Cancer, Medical Oncology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, [INFO.INFO-DB] Computer Science [cs]/Databases [cs.DB], Humans, Prospective Studies, Retrospective Studies, Minimum Data Set, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], biology, General Medicine, Genomics, Precision medicine, biology.organism_classification, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Data sharing, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Osiris
Abstract: PURPOSE Many institutions throughout the world have launched precision medicine initiatives in oncology, and a large amount of clinical and genomic data is being produced. Although there have been attempts at data sharing with the community, initiatives are still limited. In this context, a French task force composed of Integrated Cancer Research Sites (SIRICs), comprehensive cancer centers from the Unicancer network (one of Europe's largest cancer research organization), and university hospitals launched an initiative to improve and accelerate retrospective and prospective clinical and genomic data sharing in oncology. MATERIALS AND METHODS For 5 years, the OSIRIS group has worked on structuring data and identifying technical solutions for collecting and sharing them. The group used a multidisciplinary approach that included weekly scientific and technical meetings over several months to foster a national consensus on a minimal data set. RESULTS The resulting OSIRIS set and event-based data model, which is able to capture the disease course, was built with 67 clinical and 65 omics items. The group made it compatible with the HL7 Fast Healthcare Interoperability Resources (FHIR) format to maximize interoperability. The OSIRIS set was reviewed, approved by a National Plan Strategic Committee, and freely released to the community. A proof-of-concept study was carried out to put the OSIRIS set and Common Data Model into practice using a cohort of 300 patients. CONCLUSION Using a national and bottom-up approach, the OSIRIS group has defined a model including a minimal set of clinical and genomic data that can be used to accelerate data sharing produced in oncology. The model relies on clear and formally defined terminologies and, as such, may also benefit the larger international community.
Published: 2021

16. Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

Author: Kamal, Maud, Lameiras, Sonia, Deloger, Marc, Morel, Adeline, Vacher, Sophie, Lecerf, Charlotte, Dupain, C. lia, Jeannot, Emmanuelle, Girard, Elodie, Baulande, Sylvain, Dubot, Coraline, Kenter, Gemma, Jordanova, Ekaterina S., Berns, Els M. J. J., Bataillon, Guillaume, Popovic, Marina, Rouzier, Roman, Cacheux, Wulfran, le Tourneau, Christophe, Nicolas, Alain, Servant, Nicolas, Scholl, Suzy M., Bièche, Ivan, de la Rochefordiere, Anne, Fumoleau, Pierre, Mandic, Aljosa, Samet, Nina, Kamoun, Choumouss, Rondoff, Windy, Armanet, Sebastien, Rohel, Alexandra, Neffati, Souhir, Legrier, Marie-Emmanuelle, Mabiala, Sinette Ngoumou, Dureau, Sylvain, Errera, Coralie, Craina, Marius, Margan, Madalin, Samuels, Sanne, Zijlmans, Henry, Hillemanns, Peter, Dema, Sorin, Dema, Alis, Malenkovic, Goran, Djuran, Branislav, Floquet, Anne, Guyon, Frédéric, Colombo, Pierre Emmanuel, Fabbro, Michel, Kerr, Christine, Medical Oncology, Université Grenoble Alpes (UGA), Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Obstetrics and gynaecology, AII - Infectious diseases, Institut Curie [Paris], Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Leiden University Medical Center (LUMC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Université Paris-Saclay, Hôpital privé Pays de Savoie, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), ARD - Amsterdam Reproduction and Development, and Obstetrics and Gynaecology
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Hydrolases, Molecular biology, Anal Carcinoma, Virus Integration, [SDV]Life Sciences [q-bio], Uterine Cervical Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Hpv integration, Internal medicine, Chromosome instability, TP63, medicine, Humans, Papillomaviridae, 030304 developmental biology, Cervical cancer, Human papilloma virus, 0303 health sciences, Molecular medicine, business.industry, Papillomavirus Infections, virus diseases, Middle Aged, Prostate-Specific Antigen, medicine.disease, Progression-Free Survival, female genital diseases and pregnancy complications, 3. Good health, DNA Repair Enzymes, 030220 oncology & carcinogenesis, Cohort, Carcinoma, Squamous Cell, Female, Kallikreins, MACROD2 gene, business, Biomarkers
Abstract: Background Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs. Methods Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed. Results Episomal HPV was much less frequent in CC as compared to anal carcinoma (p 300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p p = 0.011). Conclusions This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.
Published: 2021

17. The kinesin KIF1C transports APC-dependent mRNAs to cell protrusions

Author: Thomas Walter, Xavier Pichon, Edouard Bertrand, Racha Chouaib, Florian Mueller, Emeline Coleno, Tianhong Wang, Marion Peter, Kazem Zibara, Arthur Imbert, Stavroula Mili, Konstadinos Moissoglu, Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris sciences et lettres (PSL)
Subjects: 0303 health sciences, Messenger RNA, RNA localization, Chemistry, RNA, RNA transport, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cell biology, 03 medical and health sciences, 0302 clinical medicine, Cytoplasm, Live cell imaging, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Kinesin, MRNA transport, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: RNA localization and local translation are important for numerous cellular functions. In mammals, a class of mRNAs localize to cytoplasmic protrusions in an APC-dependent manner, with roles during cell migration. Here, we investigated this localization mechanism. We found that the KIF1C motor interacts with APC-dependent mRNAs and is required for their localization. Live cell imaging revealed rapid, active transport of single mRNAs over long distances that requires both microtubules and KIF1C. Two color imaging directly showed single mRNAs transported by single KIF1C motors, with the 3’UTR being sufficient to trigger KIF1C-dependent RNA transport and localization. Moreover, KIF1C remained associated with peripheral, multimeric RNA clusters and was required for their formation. These results reveal an RNA transport pathway in mammalian cells, in which the KIF1C motor has a dual role both in transporting RNAs and in promoting their clustering within cytoplasmic protrusions. Interestingly, KIF1C also transports its own mRNA suggesting a possible feedback loop acting at the level of mRNA transport.
Published: 2021

18. Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium

Author: Pierre Laurent-Puig, Yan Ren, Frédérique Rachédi, Pascal Guénel, Sandya Liyanarachchi, Asta Försti, Albert de la Chapelle, Om Kulkarni, Claire Mulot, Huiling He, Federica Gemignani, Julie Guibon, Anne-Valérie Guizard, Fabienne Lesueur, Rossella Elisei, Ausrele Kesminiene, Anthony F. Herzig, Mojgan Karimi, Pierre-Emmanuel Sugier, Thérèse Truong, Delphine Bacq-Daian, Anne-Louise Leutenegger, Constance Xhaard, Daniel F. Comiskey, Celia M Pereda, Evgenia Ostroumova, Florent de Vathaire, Elisabeth Adjadj, Françoise Borson-Chazot, Jean-François Deleuze, Carole Rubino, Anne Boland-Auge, Hauke Thomsen, Elise A. Lucotte, Marie-Christine Boutron-Ruault, Juan J Lence-Anta, Rosa Ortiz, Claire Schvartz, Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Institut Jean Godinot [Reims], UNICANCER, Registre Général des Tumeurs du Calvados, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Taaone, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institute of Oncology and Radiobiology, Ohio State University [Columbus] (OSU), University of Pisa - Università di Pisa, Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], German Cancer Consortium [Heidelberg] (DKTK), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, MESRI: 2102 918823 National Institute of Ecology, NIE Agence Nationale de la Recherche, ANR: ANR‐10‐COHO‐0006 Fondation ARC pour la Recherche sur le Cancer, ARC: PGA120150202302 Ligue Contre le Cancer Fondation de France Institut National Du Cancer, INCa: 9533 Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, ANSES Mutuelle Générale de l'Education Nationale, MGEN Electricité de France, EDF: EP 2019‐01, We thank Dr Yannick Rougier and Dr Dominique Baron-Dubourdieu for providing pathological reports for the NC study, as well as Dr Sylvie Laumond, Dr Jean-Paul Grangeon (Direction des affaires sanitaires et sociales de Nouvelle-Cal?donie) and the country's provincial health authorities (DPASS Sud, DPASS Nord, DPASS Iles Loyaut?) for support during data collection in the NC study. We thank Milagros Velasco, Mae Chappe and Idalmis Infante (Institute of Oncology and Radiobiology, La Havana, Cuba) and Silvia Turcios (National Institute of Endocrinology, La Havana, Cuba) for helping in the collection of the data in the Cuban Study. We thank John Paoaafaite and Joseph Teuri who contacted and interviewed cases and controls for the study. Finally, we also thank P. Morales, J. Iltis, P. Giraud, P. Didiergeorge, M. Brisard, G. Soubiran, B. Caillou, P. Dupire, J. Ienfa, G. de Clermont, N. Cerf, B. Oddo, M. Bambridge, C. Baron, A. Mouchard-Rachet, O. Simonet, D. Lamarque, J. Vabret, J. Delacre, M.P. Darquier and J. Leninger, for their help in the collection of the cases or in the organization of study in French Polynesia. We would like to thank the Association Centre de Regroupement Informatique et Statistique en Anatomie Pathologique en Provence-Alpes-C?te d'Azur (CRISAP PACA), as well as Dr Arlette Danzon, Dr Genevi?ve Sasolas, Dr Marc Christophe Sattonnet, Dr Marc Colonna, Dr Brigitte Lacour, Dr Michel Velten, Dr Enora Clero, Dr St?phane Maillard, Dr Laurent Bailly, Dr Eug?nia Marin? Barjoan, Dr Jean-Luc Lassalle, Dr Z Hafdi-Nejjari, Dr P Delafosse, Dr Elisabeth Adjadj, Kami-Marie Moreau, Cyrielle Orenes, Laurianne Sarrazin, St?phanie Bonnay, Fr?d?rique Chatelain, Maryse Barouh, Evelyne Rapp, Julie Festra?ts, Julie Valbousquet, Yusuf Atilgan, Jean Chappellet, Lallia Bedhouche, Florent Dayet and Ziyan Fami, for their help in the collection of cases, the organization and the management of the Young-Thyr study. We acknowledge Stefano Landi for the Italian GWAS data and Subhayan Chattopadhyay and Yasmeen Niazi (Division of Molecular Genetic Epidemiology, German Cancer Research Center?DKFZ) for technical assistance in these data analysis. We are grateful to Dr Herv? Perdry for his help in using the GASTON package. The EPITHYR GWAS was supported by Institut National du Cancer (grant number 9533) and Fondation ARC (grant number PGA120150202302). The E3N cohort received support from the MGEN, Gustave Roussy and Ligue contre le cancer for its setup and maintenance. The E3N cohort was also supported by a state grant from the Agence Nationale pour la Recherche (ANR) (grant number ANR-10-COHO-0006) within the Investissement d'Avenir program and from the French Ministry of Higher Education, Research and Innovation (MESRI, grant number 2102 918823). The other participating studies were funded by Ligue Nationale Contre le Cancer, ANR, the Direction G?n?rale de la Sante, the Agence Fran?aise de S?curit? Sanitaire de l'alimentation, de l'environnement et du travail (ANSES), CHILDTHYR EEC program, and the Fondation de France. JG was the recipient of a PhD fellowship from R?gion Ile-de-France, part of OK was the recipient of a post-doc fellowship from Electricit? de France (conseil scientifique de Radioprotection d'EDF, grant EP 2019-01)., The EPITHYR GWAS was supported by Institut National du Cancer (grant number 9533) and Fondation ARC (grant number PGA120150202302). The E3N cohort received support from the MGEN, Gustave Roussy and Ligue contre le cancer for its setup and maintenance. The E3N cohort was also supported by a state grant from the Agence Nationale pour la Recherche (ANR) (grant number ANR‐10‐COHO‐0006) within the Investissement d'Avenir program and from the French Ministry of Higher Education, Research and Innovation (MESRI, grant number 2102 918823). The other participating studies were funded by Ligue Nationale Contre le Cancer, the Direction Générale de la Sante, the Agence Française de Sécurité Sanitaire de l'alimentation, and the Fondation de France. JG was the recipient of a PhD fellowship from Région Ile‐de‐France, part of OK was the recipient of a post‐doc fellowship from Electricité de France (conseil scientifique de Radioprotection d'EDF, grant EP 2019‐01)., Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, Cancer Research, Native Hawaiian or Other Pacific Islander, [SDV]Life Sciences [q-bio], Ethnic group, Genome-wide association study, 0302 clinical medicine, Gene Frequency, Informed consent, Epidemiology, thyroid cancer, Chromosomes, Human, Medicine, Prospective cohort study, Thyroid cancer, Genetics, 0303 health sciences, education.field_of_study, Incidence (epidemiology), Middle Aged, Checklist, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Pacific islanders, Female, Adult, medicine.medical_specialty, case-control study, education, Population, Biology, Pacific Islands, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Thyroid Neoplasms, Aged, 030304 developmental biology, genome-wide association study, business.industry, Case-control study, medicine.disease, Clinical trial, Case-Control Studies, Family medicine, business
Abstract: Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. Here, we conducted a genome-wide association study (GWAS) involving 1,554 cases/1,973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from the EPITHYR consortium. Our results confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 (rs334729) and 16q23.2 (rs16950982), which were associated with TSH levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. The frequency of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans and may explain part of the highest DTC incidence observed in Oceanians.Competing Interest StatementThe authors have declared no competing interest.Funding StatementINCA (grant number 9533) and ARC (grant number PGA120150202302), Ligue Nationale Contre le Cancer, Agence Nationale pour la Recherche (ANR), the Direction Generale de la Sante, the Agence Francaise de Securite Sanitaire de l alimentation, de lenvironnement et du travail (ANSES), CHILDTHYR EEC program, and the Fondation de France. JG and CX were the recipient of a PhD fellowship from Region Ile-de-France.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All participants provided informed consent and each study was approved by their governing ethics committee.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. (Less)
Published: 2021

19. Setting the basis of best practices and standards for curation and annotation of logical models in biology—highlights of the [BC]2 2019 CoLoMoTo/SysMod Workshop

Author: Denis Thieffry, Ioannis Xenarios, Sylvain Soliman, Claudine Chaouiya, Laurence Calzone, Aurélien Naldi, Julio Saez-Rodriguez, Cristina Casals-Casas, Vasundra Touré, Tomáš Helikar, Rahuman S. Malik Sheriff, Gautier Stoll, Martin Kuiper, Vincent Noël, Tom C. Freeman, Anna Niarakis, Marek Ostaszewski, Eugenia Oshurko, Paul Thomas, Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), University of Luxembourg [Luxembourg], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Swiss-Prot Group, Swiss Institute of Bioinformatics [Genève] (SIB), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Edinburgh, University of Southern California (USC), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Heidelberg University Hospital [Heidelberg], Laboratoire de l'Informatique du Parallélisme (LIP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Ludwig Institute for Cancer Research, Computational systems biology and optimization (Lifeware), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), University of Nebraska [Lincoln], University of Nebraska System, Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Soliman, Sylvain, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), University of Nebraska–Lincoln, École Pratique des Hautes Études (EPHE), and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Best practice, 0206 medical engineering, 02 engineering and technology, Plan (drawing), Logical modelling, Models, Biological, 03 medical and health sciences, Annotation, Model reusability, Annotation standards, Molecular Biology, Method Review, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, Biological data, Computational model, Computational Biology, Reproducibility of Results, Data science, Reproducibility, Variety (cybernetics), Biocuration, Practice Guidelines as Topic, Key (cryptography), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 020602 bioinformatics, Information Systems
Abstract: The fast accumulation of biological data calls for their integration, analysis and exploitation through more systematic approaches. The generation of novel, relevant hypotheses from this enormous quantity of data remains challenging. Logical models have long been used to answer a variety of questions regarding the dynamical behaviours of regulatory networks. As the number of published logical models increases, there is a pressing need for systematic model annotation, referencing and curation in community-supported and standardised formats. This article summarises the key topics and future directions of a meeting entitled ‘Annotation and curation of computational models in biology’, organised as part of the 2019 [BC]2 conference. The purpose of the meeting was to develop and drive forward a plan towards the standardised annotation of logical models, review and connect various ongoing projects of experts from different communities involved in the modelling and annotation of molecular biological entities, interactions, pathways and models. This article defines a roadmap towards the annotation and curation of logical models, including milestones for best practices and minimum standard requirements.
Published: 2021

20. Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians

Author: Elisabeth Adjadj, Om Kulkarni, Anne Boland, Jean-François Deleuze, Carole Rubino, Ausrele Kesminiene, Pascal Guénel, Pierre-Emmanuel Sugier, Julie Guibon, Anne-Valérie Guizard, Frédérique Rachédi, Thérèse Truong, Florent de Vathaire, Marie-Christine Boutron-Ruault, Mojgan Karimi, Claire Schvartz, Constance Xhaard, Delphine Bacq-Daian, Fabienne Lesueur, Evgenia Ostroumova, Pierre Laurent-Puig, Céline Besse, Yan Ren, Claire Mulot, Rosa Ortiz, BOZEC, Erwan, Cohortes - Etude Epidémiologique des Enfants de femmes de l'Education Nationale - - E4N2010 - ANR-10-COHO-0006 - COHO - VALID, Institut Gustave Roussy (IGR), Université Paris-Saclay, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital de Taaone, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Epigenetec, Centre de Ressources Biologiques (CRB), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jean Godinot [Reims], UNICANCER, Institute of Oncology and Radiobiology, International Agency for Cancer Research (IACR), This work was supported by the Institut National du Cancer (Inca grant 9533), the Fondation ARC pour la Recherche sur le Cancer (ARC grant PGA120150202302), the Centre National de Recherche en Génomique Humaine, CEA, Electricité de France (conseil scientifique de Radioprotection d’EDF, grant EP 2019-01), Fondation de France (Grant 2016-70074) and Plan Cancer (Project ThyrGenRad, Grant ENV201415). The E3N cohort received support from the MGEN, Gustave Roussy and Ligue contre le cancer for its set up and maintenance. The E3N cohort was also supported by a state grant from the Agence Nationale pour la Recherche (ANR, grant number ANR-10-COHO-0006) within the Investissement d’Avenir program, and from Ministère de l’enseignement supérieur, de la recherche et de l’innovation (MESRI, grant number 2102 918823). JG was the recipient of a PhD fellowship from Région Ile-de-France., ANR-10-COHO-0006,E4N,Etude Epidémiologique des Enfants de femmes de l'Education Nationale(2010), Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, case-control study, Population, cancer genetics, fine-mapping study, Single-nucleotide polymorphism, Genome-wide association study, Biology, Thyroid carcinoma, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, single nucleotide polymorphism, medicine, thyroid cancer, SNP, education, Thyroid cancer, Genetic association, Genetics, education.field_of_study, Case-control study, medicine.disease, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Research Paper
Abstract: International audience; Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality. At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue. Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.
Published: 2021

21. Change-point joint model for identification of plateau of activity in early phase trials

Author: Maria-Athina Altzerinakou, Xavier Paoletti, Novartis Pharma AG, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), 633567 National Cancer Institute, NCI, information French NCI, INCA-Optidose, and H2020 Marie Sk?odowska-Curie Actions, 633567
Subjects: Statistics and Probability, Maximum Tolerated Dose, Epidemiology, Inference, Antineoplastic Agents, Plateau (mathematics), 01 natural sciences, Cohort Studies, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Statistics, Medicine, Humans, Point (geometry), 030212 general & internal medicine, 0101 mathematics, Dose-Response Relationship, Drug, business.industry, cumulative toxicities, plateau identification, 3. Good health, joint modeling, Identification (information), change-point model, Research Design, Maximum tolerated dose, Cohort, Biomarker (medicine), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Immunotherapy, Early phase, business
Abstract: International audience; This article presents a phase I/II trial design for targeted therapies and immunotherapies, with the objective of identifying the optimal dose (OD). We employ a joint modeling technique for discrete time-to-event toxicity data and repeated and continuous biomarker measurements. For the biomarker measurements, we implement a change point linear mixed effects skeleton model. This model can accommodate both plateauing and nonplateauing dose-activity relationships. For each new cohort of patients, we estimate the maximum tolerated dose (MTD) taking toxicity as a cumulative endpoint, over six treatment cycles. Then, we select the OD using two different criteria. The OD is a dose that is equally active to the MTD or a dose located on the beginning of the plateau of the dose-activity relationship. Joint modeling allows us to take into account informative censoring due to toxicities or lack of activity and we also consider consent withdrawal and intermittent missing responses. Model estimation relies on likelihood inference.
Published: 2021

22. Multimodal liquid biopsy for early monitoring and outcome prediction of chemotherapy in metastatic breast cancer

Author: Charlotte Proudhon, Jérôme Lemonnier, Anthony Gonçalves, Frédérique Berger, Shufang Renault, Jean-Yves Pierga, François-Clément Bidard, Marie-Laure Tanguy, Christelle Levy, Marc Debled, Isabelle Desmoulins, Elodie Girard, Sylvain Baulande, Coraline Dubot, Christelle Jouannaud, Amanda Bortolini Silveira, Caroline Hego, Benoit Albaud, William Jacot, Maria Rios, Jean-Marc Ferrero, Florence Dalenc, Olivier Tredan, Marie-Ange Mouret-Reynier, Aurore Rampanou, CIC1428 IGR-CURIE, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Saclay, Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Departement d'Oncologie médicale [Paris], Institut du Cancer de Montpellier (ICM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'oncologie médicale, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Jean Godinot [Reims], UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), 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), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité), ANR-10-EQPX-0031,FIT,Internet du Futur (des Objets)(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), 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), COLO, Mouniati, Internet du Futur (des Objets) - - FIT2010 - ANR-10-EQPX-0031 - EQPX - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Institut Curie [Saint-Cloud], Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Paris (UP)
Subjects: Oncology, medicine.medical_specialty, Bevacizumab, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Predictive markers, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Circulating tumor cell, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Liquid biopsy, RC254-282, 030304 developmental biology, 0303 health sciences, Chemotherapy, business.industry, GATA3, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Metastatic breast cancer, 3. Good health, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Outcome prediction, business, medicine.drug
Abstract: Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are two cancer-derived blood biomarkers that inform on patient prognosis and treatment efficacy in breast cancer. We prospectively evaluated the clinical validity of quantifying both CTCs (CellSearch) and ctDNA (targeted next-generation sequencing). Their combined value as prognostic and early monitoring markers was assessed in 198 HER2-negative metastatic breast cancer patients. All patients were included in the prospective multicenter UCBG study COMET (NCT01745757) and treated by first-line chemotherapy with weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline and before the second cycle of chemotherapy. At baseline, CTCs and ctDNA were respectively detected in 72 and 74% of patients and were moderately correlated (Kendall’s τ = 0.3). Only 26 (13%) patients had neither detectable ctDNA nor CTCs. Variants were most frequently observed in TP53 and PIK3CA genes. KMT2C/MLL3 variants detected in ctDNA were significantly associated with a lower CTC count, while the opposite trend was seen with GATA3 alterations. Both CTC and ctDNA levels at baseline and after four weeks of treatment were correlated with survival. For progression-free and overall survival, the best multivariate prognostic model included tumor subtype (triple negative vs other), grade (grade 3 vs other), ctDNA variant allele frequency (VAF) at baseline (per 10% increase), and CTC count at four weeks (≥5CTC/7.5 mL). Overall, this study demonstrates that CTCs and ctDNA have nonoverlapping detection profiles and complementary prognostic values in metastatic breast cancer patients. A comprehensive liquid-biopsy approach may involve simultaneous detection of ctDNA and CTCs.
Published: 2021

23. Validation of Predictive Biomarkers With Time-to-Event Endpoint

Author: Mboup, Bassirou, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Aurélien Latouche, STAR, ABES, Mines Paris - PSL (École nationale supérieure des mines de Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Biomarqueurs, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Predictors, Cancer de l’ovaire, Immunothérapie, Ovarian Cancer, Régression quantile, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Calibration, Pronostic, Quantile regression, Immunotherapy, [MATH.MATH-ST] Mathematics [math]/Statistics [math.ST], Prédictifs, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: It is common in oncology to want to determine whether or not only a subgroup of patients will benefit from a treatment. This is one of the paradigms of personalized or stratified medicine. Predictive biomarkers are often used to select these patients and most of these biomarkers are continuous. For example genomic signatures such as Oncotype-Dx. A methodology for evaluating a biomarker with binary response has been proposed in the literature. The objective of this thesis is in first work to extend this methodology with right-censored data and to determine at different prediction horizons the optimal threshold of the biomarker beyond which treatment will be attributed or avoided. A model whose estimates of these parameters are based on inverse censored probability weights is proposed to provide consistent estimators. An extension of the predictiveness curves will be carried out. In a second work, a test of the calibration hypothesis with right-censored data has been proposed. This test will be valid beyond the 60% censoring rate contrary to those already existing in the literature and will allow us to study the influence of a bad calibration on the determination of the threshold. A third work focuses on the determination of the threshold of a new prognostic biomarker for ovarian cancer in order to classify patients at high or low risk of relapse. Finally, a fourth work consists in illustrating the relevance of the censored quantile regression for quantifying the long term benefit of immunotherapy in a reconstructed data set from a single randomized trial. The proposed methodology can be readilty employed for individual patients data meta-analysis to summarize evidence of immunotherapy as quantified by the upper quantile of the survival distribution., Il est fréquent en oncologie, de vouloir déterminer si seulement un sous groupe de patients va bénéficier ou pas d’un traitement. C’est un des paradigmes de la médecine personnalisée ou stratifiée. Les biomarqueurs prédictifs sont souvent utilisés pour sélectionner ces patients et la plupart de ces biomarqueurs sont continus. Par exemple les signatures génomiques comme Oncotype-Dx. Il a été proposé dans la littérature une méthodologie d’évaluation d’un biomarqueur avec réponse binaire. L’objectif dans cette thèse est dans un premier travail d’étendre cette méthodologie avec un critère de jugement censuré et de déterminer à différent horizons de prédiction le seuil optimal du biomarqueur au-delà duquel le traitement sera attribué ou évité. Un modèle dont l’estimation de ces paramètres repose sur des pondérations par l’inverse des probabilités de censure est proposé permettant ainsi d’obtenir un estimateur consistant. Une extension des courbes de prédictivité par bras de traitement dépendantes du temps est ainsi proposée. Dans un second travail, un test de l’hypothèse de calibration avec des données censurées à droite a été proposé. Ce test est valide au-delà 60% de taux de censure contrairement à ceux qui existe déjà dans la littérature et nous permettra d’étudier l’influence d’une mauvaise calibration sur la détermination du seuil. Un troisième travail s’intéresse à la détermination du seuil d’un nouveau biomarqueur pronostique pour le cancer de l’ovaire afin de classer les patients en haut ou bas risque de rechute. Enfin, dans un quatrième travail, nous proposons d’employer la régression quantile pour données censurées pour quantifier le bénéfice à long terme de l’immunothérapie.
Published: 2020

24. Dynamical Boolean Modeling of Immunogenic Cell Death

Author: Checcoli, Andrea, Pol, Jonathan, Naldi, Aurelien, Noël, Vincent, Barillot, Emmanuel, Kroemer, Guido, Thieffry, Denis, Calzone, Laurence, Stoll, Gautier, Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Institut Gustave Roussy (IGR), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: logical modeling, Physiology, Physiology (medical), [SDV]Life Sciences [q-bio], immunogenic cell death, cytotoxic CD8+ T lymphocytes, dendritic cells, antitumor immune response, Original Research
Abstract: International audience; As opposed to the standard tolerogenic apoptosis, immunogenic cell death (ICD) constitutes a type of cellular demise that elicits an adaptive immune response. ICD has been characterized in malignant cells following cytotoxic interventions, such as chemotherapy or radiotherapy. Briefly, ICD of cancer cells releases some stress/danger signals that attract and activate dendritic cells (DCs). The latter can then engulf and cross-present tumor antigens to T lymphocytes, thus priming a cancer-specific immunity. This series of reactions works as a positive feedback loop where the antitumor immunity further improves the therapeutic efficacy by targeting cancer cells spared by the cytotoxic agent. However, not all chemotherapeutic drugs currently approved for cancer treatment are able to stimulate bona fide ICD: some commonly used agents, such as cisplatin or 5-fluorouracil, are unable to activate all features of ICD. Therefore, a better characterization of the process could help identify some gene or protein candidates to target pharmacologically and suggest combinations of drugs that would favor/increase antitumor immune response. To this end, we have built a mathematical model of the major cell types that intervene in ICD, namely cancer cells, DCs, CD8+ and CD4+ T cells. Our model not only integrates intracellular mechanisms within each individual cell entity, but also incorporates intercellular communications between them. The resulting cell population model recapitulates key features of the dynamics of ICD after an initial treatment, in particular the time-dependent size of the different cell types. The model is based on a discrete Boolean formalism and is simulated by means of a software tool, UPMaBoSS, which performs stochastic simulations with continuous time, considering the dynamics of the system at the cell population level with appropriate timing of events, and accounting for death and division of each cell type. With this model, the time scales of some of the processes involved in ICD, which are challenging to measure experimentally, have been predicted. In addition, our model analysis led to the identification of actionable targets for boosting ICD-induced antitumor response. All computational analyses and results are compiled in interactive notebooks which cover the presentation of the network structure, model simulations, and parameter sensitivity analyses.
Published: 2020

25. CD44 regulates epigenetic plasticity by mediating iron endocytosis

Author: Bérangère Lombard, Raphaël Rodriguez, Christophe Ginestier, Tatiana Cañeque, Nicolas Servant, Emmanuelle Charafe-Jauffret, Adeline Durand, Ting-Di Wu, Céline Vallot, Anne Lafon, Damarys Loew, Sebastian Müller, Fabien Sindikubwabo, Sylvain Baulande, Antoine Versini, Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Université Paris sciences et lettres (PSL), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Rodriguez, Raphaël
Subjects: General Chemical Engineering, Iron, [SDV]Life Sciences [q-bio], Cell, Regulator, Transferrin receptor, 010402 general chemistry, Endocytosis, 01 natural sciences, Article, Epigenesis, Genetic, medicine, Humans, Epigenetics, Hyaluronic Acid, Epigenesis, biology, 010405 organic chemistry, Chemistry, CD44, General Chemistry, 0104 chemical sciences, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Histone, Hyaluronan Receptors, biology.protein
Abstract: International audience; CD44 is a transmembrane glycoprotein linked to various biological processes reliant on epigenetic plasticity, which include development, inflammation, immune responses, wound healing and cancer progression. Although it is often referred to as a cell surface marker, the functional regulatory roles of CD44 remain elusive. Here we report the discovery that CD44 mediates the endocytosis of iron-bound hyaluronates in tumorigenic cell lines, primary cancer cells and tumours. This glycan-mediated iron endocytosis mechanism is enhanced during epithelial-mesenchymal transitions, in which iron operates as a metal catalyst to demethylate repressive histone marks that govern the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron through a positive feedback loop, which is in contrast to the negative regulation of the transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis using small molecules. This study reveals an alternative iron-uptake mechanism that prevails in the mesenchymal state of cells, which illuminates a central role of iron as a rate-limiting regulator of epigenetic plasticity.
Published: 2020

26. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B.M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Antonis Antoniou, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Mary B. Daly, Miguel de la Hoya, Robin de Putter, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Bent Ejlertsen, Christoph Engel, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Patricia A. Ganz, Judy Garber, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Daphne Gschwantler-Kaulich, Eric Hahnen, Ute Hamann, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Catherine Noguès, Claudine Isaacs, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Torben A. Kruse, Ava Kwong, Yael Laitman, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Nikitina-Zake, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Darcy L. Thull, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Antonis C. Antoniou, Pediatric surgery, Human genetics, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Chapel Allerton Hospital, Great Ormond Street Hospital for Children [London] (GOSH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto (University of Toronto), Christian-Albrechts University of Kiel, The University of Texas M.D. Anderson Cancer Center [Houston], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], CIBER de Enfermedades Raras (CIBERER), Spanish National Cancer Research Center (CNIO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Pomeranian Medical University [Szczecin] (PUM), University of California (UC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], European Institute of Oncology IRCCS [Milan, Italy] (EIO), Zealand University Hospital [Roskilde, Denmark], Lund University [Lund], National Institute of Oncology [Budapest, Hungary], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Royal Devon & Exeter Hospital, Exeter, UK, Catalan Institute of Oncology [Barcelone, Espagne], Huntsman Cancer Institute [Salt Lake City], University of Utah, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Pisa University Hospital, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, Aarhus University Hospital, Columbia University [New York], Ghent University Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Sheffield Children's NHS Foundation Trust, Fox Chase Cancer Center, Queen Elizabeth University Hospital (Glasgow), Centre hospitalier universitaire de Nantes (CHU Nantes), Leiden University Medical Center (LUMC), Beckman Research Institute of the City of Hope, Abramson Cancer Center, University of Pretoria [South Africa], Centre Hospitalier Universitaire de Québec Research Center [Canada], Royal Marsden NHS Foundation Trust, Copenhagen University Hospital, Leipzig University, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Masaryk Memorial Cancer Institute (MMCI), Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), National Center for Scientific Research 'Demokritos' (NCSR), NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie], Chaim Sheba Medical Center, Tel Aviv University (TAU), Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Dana-Farber Cancer Institute [Boston], University of Würzburg, Rigshospitalet [Copenhagen], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Hospices Civils de Lyon (HCL), University of Kansas [Kansas City], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Medizinische Universität Wien = Medical University of Vienna, University of Cologne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Lancashire NHS Foundation Trust, University Hospital Leipzig, Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Mayo Clinic, NorthShore University HealthSystem [Evanston, IL, USA], The University of Chicago Medicine [Chicago], N. N. Petrov Institute of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Guy's and St Thomas' NHS Foundation Trust [London, UK], Peter MacCallum Cancer Center, East Melbourne, Peter MacCallum Cancer Center, Vilnius University [Vilnius], The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania, Stanford University School of Medicine [CA, USA], Memorial Sloane Kettering Cancer Center [New York], Cedars-Sinai Medical Center, Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Medical Center [Utrecht], Odense University Hospital [Odense, Denmark], The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital [Hong Kong] (HKSH), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], Fondation MINES ParisTech, Karolinska Institutet [Stockholm], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Amsterdam UMC - Amsterdam University Medical Center, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Radboud University Medical Center [Nijmegen], Roswell Park Cancer Institute [Buffalo], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Toronto, University Health Network, University Hospital Düsseldorf, Latvian Biomedical Research and Study Centre [Rīga], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Chicago, Birmingham Women's and Children's NHS Foundation Trust, Cambridge University Hospitals - NHS (CUH), Charité Campus Virchow-Klinikum (CVK), Università degli Studi di Firenze = University of Florence (UniFI), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Seoul National University [Seoul] (SNU), QIMR Berghofer Medical Research Institute, Aalborg University [Denmark] (AAU), IRCCS Istituto Nazionale dei Tumori [Milano], Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Klinikum rechts der Isar [Munich, Germany], University of New South Wales [Sydney] (UNSW), Garvan Institute of medical research, Technion Faculty of Medicine [Haifa, Israel], Yale School of Medicine [New Haven, Connecticut] (YSM), Vejle Hospital [Danemark], Ohio State University [Columbus] (OSU), Centre de lutte contre le cancer Paul-Strauss, Institut de Cancérologie de Strasbourg Europe (ICANS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], Princess Anne Hospital, City of Hope Comprehensive Cancer Center [Duarte], Monash University [Clayton], Cancer Council Victoria [Melbourne, VIC, Australia], Hannover Medical School [Hannover] (MHH), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Heidelberg University Hospital [Heidelberg], Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Malaysia and University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), McGill University = Université McGill [Montréal, Canada], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Gent = Ghent University (UGENT), Oxford University Hospitals NHS Trust, University of Oxford, Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital of Cologne [Cologne], Mayo Clinic [Rochester], Collaborators : Pascaline Berthet, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Julian Adlard, Munaza Ahmed, Antonis Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O'Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Peter Devilee, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Dupuis, Christine, Institut Català de la Salut, [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Barnes, Daniel [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI), Medical Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, University of Helsinki, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Pomeranian Medical University, University of California, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], University of Leipzig [Leipzig, Allemagne], Masaryk Memorial Cancer Institute (RECAMO), Tel Aviv University [Tel Aviv], University of California-University of California, University of Münster, Amsterdam UMC, Technical University of Munich (TUM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Garvan Institute of Medical Research [Sydney, Australia], Yale University School of Medicine, Vejle Hospital, University of Kansas Medical Center [Lawrence], Université Paris Descartes (Paris 5), University of Malaya [Kuala Lumpur, Malaisie], Universiteit Gent = Ghent University [Belgium] (UGENT), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], [SDV]Life Sciences [q-bio], Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], MODIFIERS, Diàtesi, SUSCEPTIBILITY, Carcinoma, Ovarian Epithelial, PRS, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Medicine and Health Sciences, Medicine, Genetics(clinical), genetics, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], BRCA1 Protein, Hazard ratio, Absolute risk reduction, 1184 Genetics, developmental biology, physiology, article, ASSOCIATION, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], ddc, 3. Good health, [SDV] Life Sciences [q-bio], ovarian cancer, 030220 oncology & carcinogenesis, Female, Cohort study, medicine.medical_specialty, Heterozygote, Population, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, MUTATION CARRIERS, Ovaris - Càncer - Aspectes genètics, Càncer de mama, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, Ovarian cancer, BRCA1/2, Internal medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], BRCA2 Protein, IDENTIFICATION, business.industry, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], Retrospective cohort study, ALLELES, medicine.disease, BRCA1, BRCA2, MODEL, PATHOLOGY, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, 3111 Biomedicine, business
Abstract: Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020

27. A Dual Protein-mRNA Localization Screen Reveals Compartmentalized Translation and Widespread Co-translational RNA Targeting

Author: Thomas Walter, Emeline Coleno, Florian Mueller, Adham Safieddine, Xavier Pichon, Nikolay Tsanov, Arthur Imbert, Marie-Cécile Robert, Aubin Samacoits, Edouard Bertrand, Racha Chouaib, Anthony A. Hyman, Kazem Zibara, Christophe Zimmer, Matthias Peter, Ina Poser, Oh Sung Kwon, Hervé Le Hir, Abdel-Meneem Traboulsi, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratory of Stem Cells [Lebanese, Beirut] (ER045-PRASE), Lebanese University [Beirut] (LU), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Equipe labellisée Ligue contre le Cancer, This project was supported by France BioImaging (ANR-10-INBS-04), the Agence Nationale de la Recherche (ANR-11-BSV8-018-02 and ANR-14-CE10-0018-01), the Institut Pasteur, the Ligue Nationale Contre le Cancer, and the Fondation pour la Recherche Médicale (FRM grant to E.B.). Furthermore, this work was supported by the French government under management of Agence Nationale de la Recherche as part of the 'Investissements d'avenir' program, reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute) and by the Labex EpiGenMed from the framework 'Investissements d’avenir.', ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-11-BSV8-0018,EJCbirth,Impacts de la transcription par l'ARN polymérase II sur l'assemblage de l'EJC(2011), ANR-14-CE10-0018,HI-FISH,Etude systématique de l'expression des gènes à l'échelle des molécules uniques d'ARN(2014), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Zimmer, Christophe, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, BLANC - Impacts de la transcription par l'ARN polymérase II sur l'assemblage de l'EJC - - EJCbirth2011 - ANR-11-BSV8-0018 - BLANC - VALID, Appel à projets générique - Etude systématique de l'expression des gènes à l'échelle des molécules uniques d'ARN - - HI-FISH2014 - ANR-14-CE10-0018 - Appel à projets générique - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, and Laboratoires d'excellence - From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow - - EpiGenMed2010 - ANR-10-LABX-0012 - LABX - VALID
Subjects: RNA localization, Endosome, ASPM, translation factories, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, General Biochemistry, Genetics and Molecular Biology, smFISH, Cell Line, 03 medical and health sciences, 0302 clinical medicine, local translation, Polysome, Gene expression, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, RNA, Messenger, Molecular Biology, Gene, 030304 developmental biology, Centrosome, 0303 health sciences, Messenger RNA, co-translational targeting Manuscript, Translation (biology), Cell Biology, Translocon, Cell biology, Protein Transport, Gene Expression Regulation, Polyribosomes, Protein Biosynthesis, Beta-catenin, RNA, RNA transport, co-translational targeting, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Local translation allows spatial control of gene expression. Here, we performed a dual protein-mRNA localization screen, using smFISH on 523 human cell lines expressing GFP-tagged genes. 32 mRNAs displayed specific cytoplasmic localizations with local translation at unexpected locations, including cytoplasmic protrusions, cell edges, endosomes, Golgi, the nuclear envelope, and centrosomes, the latter being cell-cycle-dependent. Automated classification of mRNA localization patterns revealed a high degree of intercellular heterogeneity. Surprisingly, mRNA localization frequently required ongoing translation, indicating widespread co-translational RNA targeting. Interestingly, while P-body accumulation was frequent (15 mRNAs), four mRNAs accumulated in foci that were distinct structures. These foci lacked the mature protein, but nascent polypeptide imaging showed that they were specialized translation factories. For β-catenin, foci formation was regulated by Wnt, relied on APC-dependent polysome aggregation, and led to nascent protein degradation. Thus, translation factories uniquely regulate nascent protein metabolism and create a fine granular compartmentalization of translation.
Published: 2020

28. De la modélisation mécanistique des voies de signalisation dans le cancer à l’interprétation des modèles et de leurs apports : applications cliniques et évaluation statistique

Author: Béal, Jonas, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres, Emmanuel Barillot, and Aurélien Latouche
Subjects: Biostatistiques, Inférence causale, Modélisation, Precision medicine, Modèle méchanistique, Modeling, Mechanistic model, Biostatistics, Médecine de précision, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cancer, Causal inference
Abstract: Beyond its genetic mechanisms, cancer can be understood as a network disease that often results from the interactions between different perturbations in a cellular regulatory network. The dynamics of these networks and associated signaling pathways are complex and require integrated approaches. One approach is to design mechanistic models that translate the biological knowledge of networks in mathematical terms to simulate computationally the molecular features of cancers. However, these models only reflect the general mechanisms at work in cancers.This thesis proposes to define personalized mechanistic models of cancer. A generic model is first defined in a logical (or Boolean) formalism, before using omics data (mutations, RNA, proteins) from patients or cell lines in order to make the model specific to each one profile. These personalized models can then be compared with the clinical data of patients in order to validate them. The response to treatment is investigated in particular in this thesis. The explicit representation of the molecular mechanisms by these models allows to simulate the effect of different treatments according to their targets and to verify if the sensitivity of a patient to a drug is well predicted by the corresponding personalized model. An example concerning the response to BRAF inhibitors in melanomas and colorectal cancers is thus presented.The comparison of mechanistic models of cancer, those presented in this thesis and others, with clinical data also encourages a rigorous evaluation of their possible benefits in the context of medical use. The quantification and interpretation of the prognostic value of outputs of some mechanistic models is briefly presented before focusing on the particular case of models able to recommend the best treatment for each patient according to his molecular profile. A theoretical framework is defined to extend causal inference methods to the evaluation of such precision medicine algorithms. An illustration is provided using simulated data and patient derived xenografts.All the methods and applications put forward a possible path from the design of mechanistic models of cancer to their evaluation using statistical models emulating clinical trials. As such, this thesis provides one framework for the implementation of precision medicine in oncology.; Au delà de ses mécanismes génétiques, le cancer peut être compris comme une maladie de réseaux qui résulte souvent de l’interaction entre différentes perturbations dans un réseau de régulation cellulaire. La dynamique de ces réseaux et des voies de signalisation associées est complexe et requiert des approches intégrées. Une d’entre elles est la conception de modèles dits mécanistiques qui traduisent mathématiquement la connaissance biologique des réseaux afin de pouvoir simuler le fonctionnement moléculaire des cancers informatiquement. Ces modèles ne traduisent cependant que les mécanismes généraux à l’oeuvre dans certains cancers en particulier.Cette thèse propose en premier lieu de définir des modèles mécanistiques personnalisés de cancer. Un modèle générique est d’abord défini dans un formalisme logique (ou Booléen), avant d’utiliser les données omiques (mutations, ARN, protéines) de patients ou de lignées cellulaires afin de rendre le modèle spécifique à chacun. Ces modèles personnalisés peuvent ensuite être confrontés aux données cliniques de patients pour vérifier leur validité. Le cas de la réponse clinique aux traitements est exploré en particulier dans ce travail. La représentation explicite des mécanismes moléculaires par ces modèles permet en effet de simuler l’effet de différents traitements suivant leur mode d’action et de vérifier si la sensibilité d’un patient à un traitement est bien prédite par le modèle personnalisé correspondant. Un exemple concernant la réponse aux inhibiteurs de BRAF dans les mélanomes et cancers colorectaux est ainsi proposé.La confrontation des modèles mécanistiques de cancer, ceux présentés dans cette thèse et d’autres, aux données cliniques incite par ailleurs à évaluer rigoureusement leurs éventuels bénéfices dans la cadre d’une utilisation médicale. La quantification et l’interprétation de la valeur pronostique des biomarqueurs issus de certains modèles méchanistiques est brièvement présentée avant de se focaliser sur le cas particulier des modèles capables de sélectionner le meilleur traitement pour chaque patient en fonction des ses caractéristiques moléculaires. Un cadre théorique est proposé pour étendre les méthodes d’inférence causale à l’évaluation de tels algorithmes de médecine de précision. Une illustration est fournie à l’aide de données simulées et de xénogreffes dérivées de patients.L’ensemble des méthodes et applications décrites tracent donc un chemin, de la conception de modèles mécanistiques de cancer à leur évaluation grâce à des modèles statistiques émulant des essais cliniques, proposant ainsi un cadre pour la mise en oeuvre de la médecine de précision en oncologie.
Published: 2020

29. A cis-acting mechanism mediates transcriptional memory at Polycomb target genes in mammals

Author: Dina Zielinski, Cecilia Lövkvist, Damarys Loew, Setareh Aflaki, Michel Wassef, Raphaël Margueron, Bérangère Lombard, Daniel Holoch, Tiphaine Hery, Martin Howard, Institut Curie [Paris], Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), John Innes Centre [Norwich], Biotech Research and Innovation Centre (BRIC), University of Copenhagen = Københavns Universitet (KU), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Spectrométrie de Masse Protéomique, Gestionnaire, Hal Sorbonne Université, Biotechnology and Biological Sciences Research Council (BBSRC), University of Copenhagen = Københavns Universitet (UCPH), Mines Paris - PSL (École nationale supérieure des mines de Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Transcriptional Activation, Cellular differentiation, Polycomb-Group Proteins, Context (language use), Biology, Epigenesis, Genetic, 03 medical and health sciences, Mice, 0302 clinical medicine, Transcription (biology), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Genetics, Gene silencing, Animals, Humans, Epigenetics, 030304 developmental biology, Mammals, 0303 health sciences, Polycomb Repressive Complex 2, Chromatin, Cell biology, Histone Code, Histone, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, 030217 neurology & neurosurgery
Abstract: Epigenetic inheritance of gene expression states enables a single genome to maintain distinct cellular identities. How histone modifications contribute to this process remains unclear. Using global chromatin perturbations and local, time-controlled modulation of transcription, we establish the existence of epigenetic memory of transcriptional activation for genes that can be silenced by the Polycomb group. This property emerges during cell differentiation and allows genes to be stably switched after a transient transcriptional stimulus. This transcriptional memory state at Polycomb targets operates in cis; however, rather than relying solely on read-and-write propagation of histone modifications, the memory is also linked to the strength of activating inputs opposing Polycomb proteins, and therefore varies with the cellular context. Our data and computational simulations suggest a model whereby transcriptional memory arises from double-negative feedback between Polycomb-mediated silencing and active transcription. Transcriptional memory at Polycomb targets thus depends not only on histone modifications but also on the gene-regulatory network and underlying identity of a cell. Polycomb proteins can regulate epigenetic transcriptional memory during cell differentiation. This memory operates in cis and is linked to the strength of activating inputs.
Published: 2020

30. A localization screen reveals translation factories and widespread co-translational RNA targeting

Author: Ina Poser, Xavier Pichon, Edouard Bertrand, Nikolay Tsanov, Christophe Zimmer, Emeline Coleno, Hervé Le Hir, Oh Sung Kwon, Adham Safieddine, Thomas Walter, Marie-Cécile Robert, Marion Peter, Abdel-Meneem Traboulsi, Arthur Imbert, Kazem Zibara, Florian Mueller, Aubin Samacoits, Racha Chouaib, Anthony A. Hyman, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Equipe labelisée Ligue Contre le Cancer, Laboratory of Stem Cells [Lebanese, Beirut] (ER045-PRASE), Lebanese University [Beirut] (LU), Faculty of Sciences [Lebanese University], Equipe labellisée Ligue contre le Cancer, Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation - Imaging and Modeling, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Université Paris sciences et lettres (PSL), This project was supported by France BioImaging (ANR-10-INBS-04), the Agence Nationale de la Recherche (ANR-11-BSV8-018-02 and ANR-14-CE10-0018-01), the Institut Pasteur, the Ligue Nationale Contre le Cancer and the Fondation pour la Recherche Médicale (FRM grant to EB). This work was supported by the Labex EpiGenMed, from the framework 'Investissements d’avenir'., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-14-CE10-0018,HI-FISH,Etude systématique de l'expression des gènes à l'échelle des molécules uniques d'ARN(2014), Lemesle, Marie, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Appel à projets générique - Etude systématique de l'expression des gènes à l'échelle des molécules uniques d'ARN - - HI-FISH2014 - ANR-14-CE10-0018 - Appel à projets générique - VALID, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Faculty of Sciences [Lebanese University] | Faculté des Sciences [Université Libanaise], Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Messenger RNA, RNA localization, Translation (biology), translation factories, Biology, Translocon, smFISH, Cell biology, 03 medical and health sciences, 0302 clinical medicine, local translation, Cytoplasm, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Polysome, co-translational targeting +Equal contributions, Gene expression, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, RNA transport, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Publié sur BioRxiv le 21 mai 2020 : https://www.biorxiv.org/content/10.1101/2020.05.20.106989v1; Local translation allows a spatial control of gene expression. Here, we performed a dual protein/mRNA localization screen, using smFISH on 523 human cell lines expressing GFP-tagged genes. A total of 32 mRNAs displayed specific cytoplasmic localizations, and we observed local translation at unexpected locations, including cytoplasmic protrusions, cell edges, endosomes, Golgi, the nuclear envelope and centrosomes, the latter being cell cycle dependent. Quantitation of mRNA distribution and automatic pattern classification revealed a high degree of localization heterogeneity between cells. Surprisingly, mRNA localization frequently required ongoing translation, indicating widespread co-translational RNA targeting. Interestingly, while P-body accumulation was frequent (15 mRNAs), four mRNAs accumulated in foci that were distinct structures. These foci lacked the mature protein, but nascent polypeptide imaging showed that they were specialized translation factories. For β-catenin, foci formation was regulated by Wnt, relied on APC-dependent polysome aggregation, and led to nascent protein degradation. Thus, translation factories uniquely regulate nascent protein metabolism and create a fine granular compartmentalization of translation.
Published: 2020

31. Demarcation of Topologically Associating Domains Is Uncoupled from Enriched CTCF Binding in Developing Zebrafish

Author: Yuvia A. Pérez-Rico, Emmanuel Barillot, Alena Shkumatava, Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gestionnaire, HAL Sorbonne Université 5, Mines Paris - PSL (École nationale supérieure des mines de Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Chromosome Organization, 02 engineering and technology, Biology, Genome, Article, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Binding site, lcsh:Science, Enhancer, Zebrafish, Molecular Biology, Regulation of gene expression, Multidisciplinary, Biological Sciences, 021001 nanoscience & nanotechnology, biology.organism_classification, Chromatin, Cell biology, 030104 developmental biology, CTCF, lcsh:Q, 0210 nano-technology, Sequence motif
Abstract: Summary CCCTC-binding factor (CTCF) is a conserved architectural protein that plays crucial roles in gene regulation and three-dimensional (3D) chromatin organization. To better understand mechanisms and evolution of vertebrate genome organization, we analyzed genome occupancy of CTCF in zebrafish utilizing an endogenously epitope-tagged CTCF knock-in allele. Zebrafish CTCF shares similar facets with its mammalian counterparts, including binding to enhancers, active promoters and repeat elements, and bipartite sequence motifs of its binding sites. However, we found that in vivo CTCF binding is not enriched at boundaries of topologically associating domains (TADs) in developing zebrafish, whereas TAD demarcation by chromatin marks did not differ from mammals. Our data suggest that general mechanisms underlying 3D chromatin organization, and in particular the involvement of CTCF in this process, differ between distant vertebrate species., Graphical Abstract, Highlights • Identification of CTCF occupancy in zebrafish embryos using a tagged ctcf allele • CTCF binding at promoters correlates with gene expression levels • No general CTCF enrichment at topological domain boundaries in zebrafish embryos, Biological Sciences; Chromosome Organization; Molecular Biology
Published: 2020

32. COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area

Author: Vuagnat, Perrine, Frelaut, Maxime, Ramtohul, Toulsie, Basse, Clémence, Diakité, Sarah, Noret, Aurélien, Bellesoeur, Audrey, Servois, Vincent, Héquet, Delphine, Laas, Enora, Kirova, Youlia, Cabel, Luc, Pierga, Jean-Yves, Paoletti, Xavier, Cottu, Paul, Bidard, François-Clément, Université de Picardie Jules Verne (UPJV), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Institut Curie, Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Gynécologie-Obstétrique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Département de radiothérapie oncologique [Paris], Service d'Oncologie Médicale, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de recherche translationnelle, Institut Curie [Paris], Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Published: 2020

33. Collective intelligence defines biological functions in Wikipedia as communities in the hidden protein connection network

Author: Urszula Czerwinska, Emmanuel Barillot, Andrei Zinovyev, Laura Cantini, Dima L. Shepelyansky, Klaus M. Frahm, Institut Curie [Paris], Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Information et Chaos Quantiques (LPT), Laboratoire de Physique Théorique (LPT), Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), MASTODONS-2016/2017 CNRS project APLIGOOGLE, ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-11-IDEX-0002,UNITI,Université Fédérale de Toulouse(2011), Shepelyansky, Dima, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Initiative d'excellence - Université Fédérale de Toulouse - - UNITI2011 - ANR-11-IDEX-0002 - IDEX - VALID, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and MINES ParisTech - École nationale supérieure des mines de Paris
Subjects: Proteomics, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Protein Extraction, Computer science, Social Sciences, Biochemistry, 0302 clinical medicine, Sociology, Databases, Genetic, Protein Interaction Mapping, Macromolecular Structure Analysis, Cluster Analysis, Biology (General), Biological Phenomena, Extraction Techniques, 0303 health sciences, Google matrix, Markov chains, Applied Mathematics, Simulation and Modeling, [PHYS.PHYS.PHYS-SOC-PH]Physics [physics]/Physics [physics]/Physics and Society [physics.soc-ph], Collective intelligence, Online Encyclopedias, Graph, 3. Good health, Nucleic acids, Physical Sciences, Encyclopedia, Graph (abstract data type), Protein Interaction Networks, Algorithms, Network Analysis, Research Article, Wikipedia networks, Computer and Information Sciences, Protein Structure, QH301-705.5, DNA repair, Research and Analysis Methods, World Wide Web, 03 medical and health sciences, Web page, Global network, Genetics, Mass Media, Protein Interactions, Molecular Biology, Probability, 030304 developmental biology, Internet, protein networks, Computational Biology, Proteins, Biology and Life Sciences, DNA, Gene Wiki, Communications, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Search Engine, [PHYS.PHYS.PHYS-SOC-PH] Physics [physics]/Physics [physics]/Physics and Society [physics.soc-ph], Encyclopedias, Protein Structure Networks, Mathematics, 030217 neurology & neurosurgery
Abstract: English Wikipedia, containing more than five millions articles, has approximately eleven thousands web pages devoted to proteins or genes most of which were generated by the Gene Wiki project. These pages contain information about interactions between proteins and their functional relationships. At the same time, they are interconnected with other Wikipedia pages describing biological functions, diseases, drugs and other topics curated by independent, not coordinated collective efforts. Therefore, Wikipedia contains a directed network of protein functional relations or physical interactions embedded into the global network of the encyclopedia terms, which defines hidden (indirect) functional proximity between proteins. We applied the recently developed reduced Google Matrix (REGOMAX) algorithm in order to extract the network of hidden functional connections between proteins in Wikipedia. In this network we discovered tight communities which reflect areas of interest in molecular biology or medicine and can be considered as definitions of biological functions shaped by collective intelligence. Moreover, by comparing two snapshots of Wikipedia graph (from years 2013 and 2017), we studied the evolution of the network of direct and hidden protein connections. We concluded that the hidden connections are more dynamic compared to the direct ones and that the size of the hidden interaction communities grows with time. We recapitulate the results of Wikipedia protein community analysis and annotation in the form of an interactive online map, which can serve as a portal to the Gene Wiki project., Author summary The long-standing effort for annotating protein functions from published experimental evidences is still far from being completed, partly due to a limited number of biocurators involved in it. Wikipedia was thought to be a suitable platform for the protein function curation crowdsourcing through exploiting the wisdom of the crowd principle. Starting from 2008, English Wikipedia was automatically populated with thousands of protein pages and links between them (Gene Wiki project), which created a useful and rapidly evolving knowledge resource. However, it remains unclear what is the benefit of hyperlinking protein pages with the whole Wikipedia knowledge corpus. We applied the recently introduced network analysis method, called reduced Google Matrix (REGOMAX), in order to study the structure of direct and indirect (hidden) links between protein pages through the rest of the global Wikipedia network. As expected, the network of direct links had node degree distribution approximately following the power law. In contrast, the network of hidden links was characterized by larger than expected tight communities of proteins related to their known functions, such as involvement in immune system. The “friendship network” of these protein groups can be used for automated annotations of their functions from non-protein Wikipedia pages. We estimated the size of the expert Wikipedia contributor community, specifically working on protein and associated pages, to be nearly 1000 wikipedians with primarily biomedical background. We conclude that the structure of global Wikipedia network can improve the annotation of protein functions by amplifying the wisdom of the crowd effect.
Published: 2020

34. CinéBreast-factors influencing the time to first metastatic recurrence in breast cancer: Analysis of real-life data from the French ESME MBC database

Author: Lionel Uwer, A. Gonçalves, A. Hennequin, C. Le Tourneau, Paul Gougis, Thomas Bachelot, C. Levy, Grégory Simon, William Jacot, Matthieu Carton, Corinne Tchokothe, M.-A. Mouret-Reynier, M. Saghatchian, Thierry Petit, Marc Debled, Christian Cailliot, M. Leheurteur, Audrey Mailliez, Christophe Perrin, M. Campone, Florence Dalenc, J.-C. Eymard, E. Chamorey, Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut Curie [Paris], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Curie - Saint Cloud (ICSC), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Institut du Cancer de Montpellier (ICM), Institut Bergonié [Bordeaux], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Léon Bérard [Lyon], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Centre Eugène Marquis (CRLCC), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), CRLCC Jean Godinot, Centre Paul Strauss, CRLCC Paul Strauss, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), R&D Unicancer [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CCSD, Accord Elsevier, Centre d'investigation clinique Paris Est (CIC Paris-Est), Institut Curie [Saint-Cloud], MINES ParisTech - École nationale supérieure des mines de Paris, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bureau de Recherches Géologiques et Minières (BRGM) (BRGM), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Hydrosystèmes et Bioprocédés (UR HBAN), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Biostatistics Unit, UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Biologie et écologie tropicale et méditerranéenne [2007-2010] (BETM), Université de Perpignan Via Domitia (UPVD)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Time Factors, Databases, Factual, [SDV]Life Sciences [q-bio], Estrogen receptor, Triple Negative Breast Neoplasms, Real-life data, computer.software_genre, Metastasis, 0302 clinical medicine, Breast cancer, Risk Factors, Epidemiology, 030212 general & internal medicine, Neoplasm Metastasis, skin and connective tissue diseases, Aged, 80 and over, Database, General Medicine, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Metastatic breast cancer, Progression-Free Survival, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Cohort, Original Article, Female, Metastatic recurrence, France, Adult, medicine.medical_specialty, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Median follow-up, Biomarkers, Tumor, medicine, Humans, Aged, Retrospective Studies, Growth rate, business.industry, Cancer, medicine.disease, Survival Analysis, Surgery, Neoplasm Recurrence, Local, business, computer, Follow-Up Studies
Abstract: Purpose The Time to First Metastatic Recurrence (TFMR) could be considered as an indirect reflection of the tumour growth kinetics which plays an important role in cancer. Molecular subtypes such as expression of estrogen receptor are known predictive factors of TFMR. The CinéBreast study aimed to identify predictive factors of the time to TFMR. Methods The French Epidemiological Strategy and Medical Economics (ESME) Metastatic Breast Cancer (MBC) Database (NCT03275311) was used, which contains data from a cohort of metastatic breast cancer patients from 2008 to 2016 using retrospective data collection. It is a national multi-centre database. The impact of TFMR on overall survival (OS) since first metastasis was also evaluated. Results Among 16 702 patients recorded in the ESME MBC database, 10 595 had an initially localised breast cancer with hormone receptor (HR) and HER2 status available, with a metastatic recurrence. Median follow up was 56 months. Median TFMR was 59 months (120: 24%). HER2+ and TNBC were respectively 4 times and 12 times (p, Highlights • ESME is a large-scale real-life database of 16 702 metastatic breast cancer patients. • A short time to first metastatic recurrence is associated with poor overall survival. • Triple-negative tumours were more likely to recur early than HR+ and HER2+ tumours.
Published: 2020

35. From single-arm studies to externally controlled studies. Methodological considerations and guidelines

Author: Xavier Paoletti, Matthieu Roustit, Florence Binlich, Bruno Laviolle, Cécile Fouret, Jehan-Michel Behier, Olivier Delaitre, Silvy Laporte, Houda Miadi-Fargier, Serge Bureau, Catherine Cornu, Nathalie Varoqueaux, Anne d’Andon, Tabassome Simon, Michel Cucherat, Natalie Hoog Labouret, Eric Vicaut, Jérémie Westerloppe, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches SERVIER (IRS), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Medtronic SNT, Medtronic, Institut national du cancer [Boulogne] (INCA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Bayer HealthCare Pharmaceuticals Inc [Whippany], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Bristol-Myers Squibb Company, INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord
Subjects: Non-comparative, Relation (database), Computer science, As is, [SDV]Life Sciences [q-bio], Guidelines as Topic, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Bias, medicine, Humans, Pharmacology (medical), Predicable, Attrition, External control study, Reliability (statistics), Randomized Controlled Trials as Topic, Protocol (science), Clinical Trials as Topic, Control group, Indirect comparison, Reproducibility of Results, Gold standard (test), Formal methods, medicine.disease, 3. Good health, Risk analysis (engineering), Single-arm study, Research Design, Matching-adjusted indirect comparisons
Abstract: International audience; Single-arm studies are sometimes used as pivotal studies but they have methodological limitations which prevent them from obtaining the high level of reliability as for a randomised controlled study which remains the gold standard in the evaluation of new treatments. The objective of this roundtable was to discuss the limitations of these single-arm studies, to analyse available and acceptable solutions in order to propose guidelines for their conduct and assessment. Single-arm studies themselves are intrinsically inappropriate for demonstrating the benefit of a new treatment because it is impossible to infer the benefit from a value obtained under treatment without knowing what it would have been in the absence of the new treatment. The implication is that comparison with other data is necessary. However this comparison has limitations due to (1) the post hoc choice of the reference used for comparison, (2) the confusion bias for which an adjustment approach is imperative and, (3) the other biases, measure and attrition among others. When these limitations are taken into account this should, first and foremost, lead to the conduct of externally controlled trials instead of single-arm trials as is proposed by the latest version of ICH E10. Moreover, the external control must be formalised in the study protocol with a priori selection of both the reference control and the formal method of comparison test in relation to a standard, adjustment on individual data, a synthetic control group or matching-adjusted indirect comparisons (MAIC). Lastly, externally controlled studies must be restricted to situations where randomisation is infeasible. To be acceptable, these studies must be able to guarantee freedom from residual confusion bias, which is only truly acceptable if the observed effect is dramatic and the usual course of the disease is highly predicable.
Published: 2020

36. Des études mono-bras aux études de comparaison externe. Considérations méthodologiques et recommandations

Author: Florence Binlich, Silvy Laporte, Houda Miadi-Fargier, Jérémie Westerloppe, Jehan-Michel Behier, Olivier Delaitre, Catherine Cornu, Anne d’Andon, Natalie Hoog Labouret, Xavier Paoletti, Eric Vicaut, Nathalie Varoqueaux, Tabassome Simon, Bruno Laviolle, Matthieu Roustit, Michel Cucherat, Cécile Fouret, Serge Bureau, Jonchère, Laurent, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Service Hospitalo-Universitaire de Pharmacotoxicologie [Lyon], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Boehringer Ingelheim France S.A.S., Celgene [Paris La Défense], Cemka-eval [Bourg La Reine], Institut de Recherches Internationales Servier [Suresnes] (IRIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Medtronic SNT, Medtronic, Institut national du cancer [Boulogne] (INCA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Bayer HealthCare Pharmaceuticals Inc [Whippany], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Unité de Recherche Clinique de l’Est Parisien [CHU Saint-Antoine] (URC-EST), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AstraZeneca [Courbevoie], Unité de Recherche Clinique (Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [APHP]), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bristol-Myers Squibb [Rueil-Malmaison], Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches SERVIER (IRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Bristol-Myers Squibb Company, Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Ingénierie et Santé (CIS-ENSMSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: [SDV] Life Sciences [q-bio], 03 medical and health sciences, Étude de contrôle externe, 0302 clinical medicine, Non-comparative, Comparaisons indirectes ajustées, Groupe contrôle, [SDV]Life Sciences [q-bio], Études mono-bras, Comparaison indirecte, Pharmacology (medical), 030226 pharmacology & pharmacy, ComputingMilieux_MISCELLANEOUS
Abstract: National audience; Les études mono-bras sont parfois utilisées comme études pivots mais elles présentent des limites méthodologiques qui ne leur permettent pas d’obtenir un niveau de fiabilité élevé comme peut l’être celui de l’essai contrôlé randomisé qui reste le standard de l’évaluation des nouveaux traitements. L’objectif de cette table ronde était de discuter des limites de ces études, d’analyser les solutions disponibles et acceptables afin de proposer des recommandations pour leur réalisation et leur évaluation. Les études mono-bras proprement dites sont intrinsèquement inadaptées pour démontrer le bénéfice d’un nouveau traitement car il est impossible de déduire ce bénéfice à partir d’une valeur sous traitement sans connaître ce qu’elle aurait été en l’absence du nouveau traitement. Une comparaison avec d’autres données est alors implicite. Cependant, cette comparaison est limitée par (1) le choix post-hoc de la référence de la comparaison, (2) le biais de confusion qui nécessite impérativement une approche d’ajustement, et (3) les autres biais, de mesure et d’attrition entres autres. La prise en considération de ces limites devrait conduire, avant tout, à la réalisation d’essais à contrôle externe (« externally controlled trial ») à la place des essais mono-bras comme le propose la dernière version d’ICH E10. Par ailleurs, la comparaison externe doit être formalisée dans le protocole de l’étude avec un choix a priori de la référence de comparaison ainsi que la méthode de comparaison formelle : test par rapport à une norme, ajustement avec des données individuelles, groupe contrôle synthétique ou « matching-adjusted indirect comparisons (MAIC) ». Finalement, l’essai de comparaison externe doit être réservé aux situations où la randomisation est irréalisable. Pour être acceptable, ces études doivent pouvoir donner la garantie d’absence de biais de confusion résiduelle, ce qui n’est vraiment recevable que si l’effet observé est extrêmement important et l’évolution de la maladie fortement prévisible.
Published: 2020

37. Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution

Author: Marie-Ming Aynaud, Olivier Mirabeau, Nadege Gruel, Sandrine Grossetête, Valentina Boeva, Simon Durand, Didier Surdez, Olivier Saulnier, Sakina Zaïdi, Svetlana Gribkova, Aziz Fouché, Ulykbek Kairov, Virginie Raynal, Franck Tirode, Thomas G.P. Grünewald, Mylene Bohec, Sylvain Baulande, Isabelle Janoueix-Lerosey, Jean-Philippe Vert, Emmanuel Barillot, Olivier Delattre, Andrei Zinovyev, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Computer Science [ETH Zürich] (D-INFK), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Nazarbayev University [Kazakhstan], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Google Brain, Paris, ITMO Cancer SysBio program (MOSAIC project, Nb bio 2014-2), Ministry of Education and Science of the Republic of Kazakhstan, grant 'Pan-cancer deconvolution of omics data using Independent Component Analysis' (IRN: AP05135430), German Cancer Aid (DKH-70112257), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), European Project: 826121,iPaediatricCurie, European Project: ERA-649,PRAVABES, European Project: 602856,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,EEC(2013), Zinovyev, Andrei, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Equipements d'excellence - Equipement de biologie intégrative du cancer pour une médecine personnalisée - - ICGex2010 - ANR-10-EQPX-0003 - EQPX - VALID, European Union’s Horizon 2020 program (grant No. 826121, iPC project) - iPaediatricCurie - 826121 - INCOMING, NET TRANSCAN JTC-2011 - PRAVABES - ERA-649 - INCOMING, EURO EWING Consortium – International Clinical Trials to Improve Survival from Ewing Sarcoma - EEC - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602856 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), MINES ParisTech - École nationale supérieure des mines de Paris, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Transcription, Genetic, EWSR1-FLI1, fungi, intratumor heterogeneity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Independent Component Analysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Gene Expression Regulation, Neoplastic, transcriptomics, lcsh:Biology (General), [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Humans, single-cell RNA-sequencing, RNA-Binding Protein EWS, patient-derived xenografts, time series, lcsh:QH301-705.5, Ewing sarcoma, Signal Transduction
Abstract: EWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive how genetically homogeneous EwS cells can drive the heterogeneity of transcriptional programs. Here, we combine independent component analysis of single-cell RNA sequencing data from diverse cell types and model systems with time-resolved mapping of EWSR1-FLI1 binding sites and of open chromatin regions to characterize dynamic cellular processes associated with EWSR1-FLI1 activity. We thus define an exquisitely specific and direct enhancer-driven EWSR1-FLI1 program. In EwS tumors, cell proliferation and strong oxidative phosphorylation metabolism are associated with a well-defined range of EWSR1-FLI1 activity. In contrast, a subpopulation of cells from below and above the intermediary EWSR1-FLI1 activity is characterized by increased hypoxia. Overall, our study reveals sources of intratumoral heterogeneity within EwS tumors., Cell Reports, 30 (6), ISSN:2666-3864, ISSN:2211-1247
Published: 2020
Full Text: View/download PDF

38. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

Author: Petra ter Brugge, Laetitia Fuhrmann, Fabien Reyal, Rania El-Botty, Thibaut Larcher, Laura Sourd, Sophie Château-Joubert, Agnès Noël, Jean-Luc Servely, Léa Huguet, Ivan Bièche, Pierre Foidart, Jos Jonkers, Philippe La Rosa, Pierre Painsec, Sophie Leboucher, Ludivine Morisset, Fariba Nemati, Georges Lucotte, Elodie Montaudon, Didier Decaudin, Christopher R. Mueller, Florence Coussy, Ahmed Dahmani, Marc-Henri Stern, Marie-France Poupon, Nor Eddine Sounni, Sophie Vacher, Adrien Briaux, Yves Pommier, Anne Vincent Salomon, Elisabetta Marangoni, Cécile Reyes, Tatiana Popova, Translational Research Department,Medical Oncology Department, Genetics Department, Institut Curie, Translational Research Department, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), PSL Research University, UMR3306, Département Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genetics Department, University of Santiago de Compostela, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), U830, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), Université de Liège, Translational Research Department, Medical Oncology Department, Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Surgery Department, CRLCC Paul Strauss, U932, Immunity and Cancer, Queen's cancer reserach institute, Queen's University, Division of Molecular Pathology and Cancer Genomics Centre Netherlands, Netherlands Cancer Institute, Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, ProdInra, Archive Ouverte, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade de Santiago de Compostela [Spain] (USC ), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), PSL Research University, U900, and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes
Subjects: Anthracycline, DNA repair, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Triple Negative Breast Neoplasms, Topoisomerase-I Inhibitor, Irinotecan, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, CHEK1, skin and connective tissue diseases, 030304 developmental biology, 0303 health sciences, biology, Retinoblastoma, business.industry, Topoisomerase, Nuclear Proteins, General Medicine, medicine.disease, eye diseases, 3. Good health, [SDV] Life Sciences [q-bio], Retinoblastoma Binding Proteins, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Topoisomerase I Inhibitors, business, Schlafen family member 11, medicine.drug
Abstract: Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.
Published: 2020

39. From the mechanistic modeling of signaling pathways in cancer to the interpretation of models and their contributions : clinical applications and statistical evaluation

Author: Béal, Jonas, STAR, ABES, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres, Emmanuel Barillot, Aurélien Latouche, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Biostatistiques, Inférence causale, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Modélisation, Precision medicine, Modèle méchanistique, Modeling, Mechanistic model, Biostatistics, Médecine de précision, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cancer, Causal inference
Abstract: Beyond its genetic mechanisms, cancer can be understood as a network disease that often results from the interactions between different perturbations in a cellular regulatory network. The dynamics of these networks and associated signaling pathways are complex and require integrated approaches. One approach is to design mechanistic models that translate the biological knowledge of networks in mathematical terms to simulate computationally the molecular features of cancers. However, these models only reflect the general mechanisms at work in cancers.This thesis proposes to define personalized mechanistic models of cancer. A generic model is first defined in a logical (or Boolean) formalism, before using omics data (mutations, RNA, proteins) from patients or cell lines in order to make the model specific to each one profile. These personalized models can then be compared with the clinical data of patients in order to validate them. The response to treatment is investigated in particular in this thesis. The explicit representation of the molecular mechanisms by these models allows to simulate the effect of different treatments according to their targets and to verify if the sensitivity of a patient to a drug is well predicted by the corresponding personalized model. An example concerning the response to BRAF inhibitors in melanomas and colorectal cancers is thus presented.The comparison of mechanistic models of cancer, those presented in this thesis and others, with clinical data also encourages a rigorous evaluation of their possible benefits in the context of medical use. The quantification and interpretation of the prognostic value of outputs of some mechanistic models is briefly presented before focusing on the particular case of models able to recommend the best treatment for each patient according to his molecular profile. A theoretical framework is defined to extend causal inference methods to the evaluation of such precision medicine algorithms. An illustration is provided using simulated data and patient derived xenografts.All the methods and applications put forward a possible path from the design of mechanistic models of cancer to their evaluation using statistical models emulating clinical trials. As such, this thesis provides one framework for the implementation of precision medicine in oncology., Au delà de ses mécanismes génétiques, le cancer peut être compris comme une maladie de réseaux qui résulte souvent de l’interaction entre différentes perturbations dans un réseau de régulation cellulaire. La dynamique de ces réseaux et des voies de signalisation associées est complexe et requiert des approches intégrées. Une d’entre elles est la conception de modèles dits mécanistiques qui traduisent mathématiquement la connaissance biologique des réseaux afin de pouvoir simuler le fonctionnement moléculaire des cancers informatiquement. Ces modèles ne traduisent cependant que les mécanismes généraux à l’oeuvre dans certains cancers en particulier.Cette thèse propose en premier lieu de définir des modèles mécanistiques personnalisés de cancer. Un modèle générique est d’abord défini dans un formalisme logique (ou Booléen), avant d’utiliser les données omiques (mutations, ARN, protéines) de patients ou de lignées cellulaires afin de rendre le modèle spécifique à chacun. Ces modèles personnalisés peuvent ensuite être confrontés aux données cliniques de patients pour vérifier leur validité. Le cas de la réponse clinique aux traitements est exploré en particulier dans ce travail. La représentation explicite des mécanismes moléculaires par ces modèles permet en effet de simuler l’effet de différents traitements suivant leur mode d’action et de vérifier si la sensibilité d’un patient à un traitement est bien prédite par le modèle personnalisé correspondant. Un exemple concernant la réponse aux inhibiteurs de BRAF dans les mélanomes et cancers colorectaux est ainsi proposé.La confrontation des modèles mécanistiques de cancer, ceux présentés dans cette thèse et d’autres, aux données cliniques incite par ailleurs à évaluer rigoureusement leurs éventuels bénéfices dans la cadre d’une utilisation médicale. La quantification et l’interprétation de la valeur pronostique des biomarqueurs issus de certains modèles méchanistiques est brièvement présentée avant de se focaliser sur le cas particulier des modèles capables de sélectionner le meilleur traitement pour chaque patient en fonction des ses caractéristiques moléculaires. Un cadre théorique est proposé pour étendre les méthodes d’inférence causale à l’évaluation de tels algorithmes de médecine de précision. Une illustration est fournie à l’aide de données simulées et de xénogreffes dérivées de patients.L’ensemble des méthodes et applications décrites tracent donc un chemin, de la conception de modèles mécanistiques de cancer à leur évaluation grâce à des modèles statistiques émulant des essais cliniques, proposant ainsi un cadre pour la mise en oeuvre de la médecine de précision en oncologie.
Published: 2020

40. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers

Author: Mavaddat, N., Antoniou, A.C., Mooij, T.M., Hooning, M.J., Heemskerk-Gerritsen, B.A., Nogues, C., Laborde, L., Breysse, E., Stoppa-Lyonnet, D., Gauthier-Villars, M., Buecher, B., Caron, O., Fourme-Mouret, E., Fricker, J.P., Lasset, C., Bonadona, V., Berthet, P., Faivre, L., Luporsi, E., Mari, V., Gladieff, L., Gesta, P., Sobol, H., Eisinger, F., Longy, M., Dugast, C., Colas, C., Coupier, I., Pujol, P., Corsini, C., Lortholary, A., Vennin, P., Adenis, C., Nguyen, T.D., Delnatte, C., Tinat, J., Tennevet, I., Limacher, J.M., Maugard, C., Bignon, Y.J., Demange, L., Penet, C., Dreyfus, H., Cohen-Haguenauer, O., Venat-Bouvet, L., Leroux, D., Zattara-Cannoni, H., Fert-Ferrer, S., Bera, O., Ellis, S., Barrowdale, D., Frost, D., Evans, D.G., Izatt, L., Adlard, J., Eeles, R., Brewer, C., Tischkowitz, M., Henderson, A., Cook, J., Eccles, D., Hogervorst, F.B.L., Collee, J.M., Asperen, C.J. van, Mensenkamp, A.R., Ausems, M.G.E.M., Meijers-Heijboer, H.E.J., Engelen, K. van, Blok, M.J., Oosterwijk, J.C., Verloop, J., Broek, E. van den, Mourits, M.J.E., Koppert, L.B., Hopper, J.L., John, E.M., Chung, W.K., Andrulis, I.L., Daly, M.B., Buys, S.S., Benitez, J., Caldes, T., Jakubowska, A., Simard, J., Singer, C.F., Tan, Y., Olah, E., Navratilova, M., Foretova, L., Gerdes, A.M., Roos-Blom, M.J., Leeuwen, F.E. van, Arver, B., Olsson, H., Schmutzler, R.K., Engel, C., Kast, K., Phillips, K.A., Terry, M.B., Milne, R.L., Goldgar, D.E., Rookus, M.A., Andrieu, N., Easton, D.F., GENEPSO, EMBRACE, HEBON, kConFab Investigators, IBCCS, kConFab, BCFR, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Erasmus MC Cancer Institute, Rotterdam, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Curie [Paris], Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Catherine-de-Sienne [Nantes] (CCS), Manchester University NHS Foundation Trust (MFT), Guy's & St Thomas' NHS Foundation Trust, Chapel Allerton Hospital, University of Leeds, Royal Marsden NHS Foundation Trust, Royal Devon & Exeter Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Sheffield Children's NHS Foundation Trust, Wessex clinical genetics service, Vrije Universiteit Amsterdam [Amsterdam] (VU), University Medical Center Groningen [Groningen] (UMCG), Department of Medical Genetics, University Medical Center [Utrecht], Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia, Department of Epidemiology, Cancer Prevention Institute of California, Columbia University [New York], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Division of Population Science, Fox Chase Cancer Center, Department of Internal Medicine, Huntsman Cancer Institute, Departemento Genetica Humana, Centro Nacional Investigaciones Oncologicas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Department of Genetics and Pathology, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Medizinische Universität Wien = Medical University of Vienna, National Institute of Oncology, Masaryk Memorial Cancer Institute (MMCI), Masaryk University [Brno] (MUNI), Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, The Netherlands Cancer Institute [Amsterdam, The Netherlands], Radiumhemmet, Karolinska University Hospital [Stockholm], Department of Oncology, Lund University Hospital, Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center Un, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Department of Epidemiology [Columbia University], Columbia University [New York]-Columbia Mailman School of Public Health, Cancer Epidemiology Centre, Cancer Council Victoria, International Agency for Cancer Research (IACR), Netherlands Cancer Institute, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Andrieu, Nadine, Human genetics, Epidemiology and Data Science, Mavaddat, Nasim [0000-0003-0307-055X], Eeles, Ros [0000-0002-3698-6241], Engel, Christoph [0000-0002-7247-282X], Apollo - University of Cambridge Repository, Pomeranian Medical University-International Hereditary Cancer Centre, Masaryk Memorial Cancer Institute (RECAMO), Columbia Mailman School of Public Health-Columbia University [New York], Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Antoniou, Antonis [0000-0001-9223-3116], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Medical Oncology, Surgery, Cancer Research UK (Reino Unido), NIH - National Cancer Institute (NCI) (Estados Unidos), United States Department of Health and Human Services, Ministerio de Economía y Competitividad (España), Unión Europea. Comisión Europea. European Research Council (ERC), Norwegian EEA Financial Mechanism, Hungarian Scientific Research Fund (Hungría), Ministry of Education, Youth and Sports (República Checa), MH CZ -DRO (MMCI), National Health and Medical Research Council (Australia), Australian National Breast Cancer Foundation, Cancer Australia, ERA-NET TRANSAN JTC 2012 Cancer, Transcan grant, Biotechnology and Biological Sciences Research Council (Reino Unido), Pink Ribbons Project, Netherlands Organisation of Scientific Research, Dutch Cancer Society (Holanda), Instituto de Salud Carlos III, Deutsche Krebshilfe, National Institute for Health Research (Reino Unido), Unión Europea. Comisión Europea. 7 Programa Marco, Ministry of Economic Development, Innovation and Export Trade-grant, Canadian Institutes of Health Research, Cancer Research UK, NIH National Cancer Institute (NCI), United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Ministerio de Economia y Competividad (MINECO), European Research Council (ERC), Hungarian Research Grants, MEYS -NPS I, National Health and Medical Research Council of Australia, BBMRI grant, Pink Ribbon grants, Netherlands Organisation of Scientific Research grant, KWF Kankerbestrijding, Instituto de Salud Carlos III - ISCIII, National Institute for Health Research (NIHR), European Union Seventh Framework Program (2007-2013), Canadian Institutes of Health Research (CIHR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), United States of Department of Health & Human Services, European Research Council, APH - Quality of Care, APH - Methodology, Graduate School, ARD - Amsterdam Reproduction and Development, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: endocrine system diseases, SURGERY, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Cohort Studies, 0302 clinical medicine, BRCA2 Mutation, Breast cancer, Surgical oncology, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Salpingo-oophorectomy/methods, 0303 health sciences, Natural menopause, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics, BRCA1 Protein, Breast Neoplasms/epidemiology, Incidence (epidemiology), Incidence, WOMEN, ASSOCIATION, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, OVARIAN, BRCA2 Protein/genetics, 3. Good health, Menopause, Risk-reducing salpingo-oophorectomy, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SURVIVAL, Female, Research Article, Cohort study, Adult, medicine.medical_specialty, Salpingo-oophorectomy, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, lcsh:RC254-282, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, METAANALYSIS, 030304 developmental biology, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, CONSORTIUM, risk-reducing salpingo-oophorectomy, International Agencies, medicine.disease, BRCA1, BRCA2, KCONFAB, REDUCTION, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, LINK, Mutation, BRCA1 Protein/genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Risk Reduction Behavior
Abstract: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO. The BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. CNIO was partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare Diseases (CIBERER). CNIO was also partially supported by FISPI16/00440. INHERIT was supported by the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program-grant #CRN-87521-and the Ministry of Economic Development, Innovation and Export Trade-grant #PSR-SIIRI-701. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministere de l'Economie, de la Science et de l' Innovation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. Jacques Simard is a Chairholder of the Canada Research Chair in Oncogenetics. EMBRACE is supported by the Cancer Research UK grants C1287/A23382 and C1287/A16563. D. Gareth Evans is supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by the Cancer Research UK grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Antonis C. Antoniou is funded by Cancer Research UK grants C12292/A20861 and C12292/A11174. MT is funded by the European Union Seventh Framework Program (2007-2013)/European Research Council (310018). The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837, Rita K. Schmutzler). The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France and the Ligue Nationale Contre le Cancer and is being supported by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, no. 2014-008). HCSC was supported by CIBERONC 161200301 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. The IHCC was supported by Grant PBZ_ KBN_122/P05/2004 and ERA-NET TRANSAN JTC 2012 Cancer 12-054 (ERA-NET-TRANSCAN/07/2014). This work was supported by grants to kConFab and the kConFab Follow-Up Study from Cancer Australia (809195); the Australian National Breast Cancer Foundation (IF 17); the National Health and Medical Research Council (454508, 288704, 145684); the National Institute of Health U.S.A. (1RO1CA159868); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; and the Cancer Foundation of Western Australia. KAP is an Australian National Breast Cancer Foundation fellow. MODSQUAD-Czech Republic, Brno, was supported by MH CZ -DRO (MMCI, 00209805) and by MEYS -NPS I -LO1413 to LF and MN. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, NKFI OTKA K-112228, and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. Lund-BRCA collaborators are supported by the Swedish Cancer Society, Lund Hospital Funds, and European Research Council Advanced Grant ERC-2011-294576. Stockholm-BRCA collaborators are supported by the Swedish Cancer Society. The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Sí
Published: 2020

41. Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer

Author: Géraldine Pignot, Sophie Vacher, Elodie Girard, Constance Le Goux, Virginie Firlej, Maud Kamal, Ivan Bièche, Simon Garinet, Diane Damotte, Julien Masliah Planchon, Grégory Thomson, Yves Allory, Voreak Suybeng, Walid Chemlali, Anne Schnitzler, Gestionnaire, HAL Sorbonne Université 5, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Plateforme de Ressources Biologiques [Henri Mondor AP-HP, Créteil] (PRB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Service d'Anatomie et de cytologie pathologiques [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Curie [Paris], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Genome instability, Cancer Research, Somatic cell, clinical biomarkers, non-coding mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Gene mutation, urologic and male genital diseases, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Gene, Palindromic sequence, genomic instability signature, Bladder cancer, Microsatellite instability, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Head and neck squamous-cell carcinoma, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, bladder cancer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Numerous pan-genomic studies identified alterations in protein-coding genes and signaling pathways involved in bladder carcinogenesis, while non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We have previously identified in bladder tumors two non-coding mutational hotspots occurring at high frequencies (&ge, 30%). These mutations are located close to the GPR126 and PLEKHS1 genes, at the guanine or the cytosine of a TGAACA core motif flanked, on both sides, by a stretch of palindromic sequences. Here, we hypothesize that such a pattern of recurrent non-coding mutations could be a signature of somatic genomic instability specifically involved in bladder cancer. We analyzed 26 additional mutable non-coding sites with the same core motif in a cohort of 103 bladder cancers composed of 44 NMIBC cases and 59 MIBC cases using high-resolution melting (HRM) and Sanger sequencing. Five bladder cancers were additionally analyzed for protein-coding gene mutations using a targeted NGS panel composed of 571 genes. Expression levels of three members of the APOBEC3 family genes were assessed using real-time quantitative RT-PCR. Non-coding somatic mutations were observed for at least one TGAACA core motif locus in 62.1% (64/103) of bladder tumor samples. These non-coding mutations co-occurred in the bladder tumors but were absent in prostate tumor, HPV-positive Head and Neck Squamous Cell Carcinoma, and high microsatellite instability (MSI-H) colorectal tumor series. This signature of palindromic non-coding somatic mutations, specific to bladder tumors, was not associated with patients&rsquo, outcome and was more frequent in females. Interestingly, this signature was associated with high tumor mutational burden (TMB) and high expression levels of APOBEC3B and interferon inducible genes. We identified a new type of somatic genomic instability targeting the TGAACA core motif loci flanked by palindromic sequences in bladder cancer. This mutational signature is a promising candidate clinical biomarker for the early detection of relapse and a major low-cost alternative to the TMB to monitor the response to immunotherapy for bladder cancer patients.
Published: 2020

42. Synthesis and Simulation of Ensembles of Boolean Networks for Cell Fate Decision

Author: Laurence Calzone, Andrei Zinovyev, Vincent Noël, Loïc Paulevé, Stéphanie Chevalier, Bioinformatique (LRI) (BioInfo - LRI), Laboratoire de Recherche en Informatique (LRI), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lobachevsky State University [Nizhni Novgorod], Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), ITMO Cancer, Ministry of Science and Higher Education of the Russian Federation (project No.14.Y26.31.0022), Plafrim, ANR-16-CE12-0034,AlgoReCell,Modèles informatiques et algorithmes pour la prédiction de cibles de reprogrammation cellulaire avec haute fidélité et haute efficacité(2016), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE12-0034,AlgoReCell,Computational Models and Algorithms for Predicting Cell Reprogramming Determinants with High Efficiency and High Fidelity(2016), ANR: PRAIRIE IA,ANR-19-P3IA-0001, Paulevé, Loïc, Modèles informatiques et algorithmes pour la prédiction de cibles de reprogrammation cellulaire avec haute fidélité et haute efficacité - - AlgoReCell2016 - ANR-16-CE12-0034 - AAPG2016 - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], [INFO.INFO-SY] Computer Science [cs]/Systems and Control [cs.SY], 050101 languages & linguistics, Single model, Computer science, 05 social sciences, Multitude, Experimental data, 02 engineering and technology, Cell fate determination, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Lead (geology), 0202 electrical engineering, electronic engineering, information engineering, [INFO.INFO-SY]Computer Science [cs]/Systems and Control [cs.SY], 020201 artificial intelligence & image processing, 0501 psychology and cognitive sciences, Biochemical engineering, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Biological network, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; The construction of models of biological networks from prior knowledge and experimental data often leads to a multitude of candidate models. Devising a single model from them can require arbitrary choices, which may lead to strong biases in subsequent predictions. We introduce here a methodology for a) synthesizing Boolean model ensembles satisfying a set of biologically relevant constraints and b) reasoning on the dynamics of the ensembles of models. The synthesis is performed using Answer-Set Programming, extending prior work to account for solution diversity and universal constraints on reachable fixed points, enabling an accurate specification of desired dynamics. The sampled models are then simulated and the results are aggregated through averaging or can be analyzed as a multi-dimensional distribution. We illustrate our approach on a previously published Boolean model of a molecular network regulating the cell fate decisions in cancer progression. It appears that the ensemble-based approach to Boolean modelling brings new insights on the variability of synergistic interacting mutations effect concerning propensity of a cancer cell to metastasize.
Published: 2020

43. Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors

Author: Sonia Lameiras, Pamela Caudana, Sylvain Baulande, Arnault Tauziède-Espariat, Nicolas Servant, Franck Bourdeaut, Amaury Leruste, Joshua J. Waterfall, Didier Surdez, Mamy Andrianteranagna, Stéphanie Puget, Sandrine Grossetête-Lalami, Eliane Piaggio, Christine Sedlik, Jimena Tosello, Mylène Bohec, Philippe Benaroch, Rodrigo Nalio Ramos, Celio Pouponnot, Jovan Nikolic, Julie Helft, Solene Brohard, Valeria Manriquez, Louise Galmiche, Leticia Laura Niborski, Olivier Delattre, Aurore Coulomb, Zhi-Yan Han, Céline Chauvin, Kevin Beccaria, Julien Masliah-Planchon, Wilfrid Richer, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris sciences et lettres (PSL), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathology Department [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Gene and Cell Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Sorbonne Paris Cité, Immunité et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, This work was funded by the BMS and the Janssen Horizon Foundations, the Société Française des Cancers de l’Enfant (SFCE) with the associations 'Enfants et Santé' and 'L’Étoile de Martin,' INCA PL-BIO 2016 call for Project from the French Minister of Research, the 'Abigael,' 'ADAM,' 'Au Nom d’Andréa,' and 'Marabout de Ficelles' associations. RTOP team is supported by the SiRIC-Curie Program (grant INCa-DGOS-4654). INSERM U830 is supported by the Institut National de la Santé et de la Recherche Médicale, Curie Institute and the Ligue Nationale Contre Le Cancer. TransImm team is supported by the SiRIC-Curie Program (grant INCa-DGOS-12554), the LabEx DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043), and the Center of Clinical Investigation (CIC IGR-Curie 1428). A.L. and P.C. were supported by the PhD program of Curie Institute., The authors thank S. Cairo, M. Chicard, J. Denizeau, C. Goudot, P. Gueguen, I. Jimenez, N. Manel, A. Pinto, S. Viel, S. Zaidi, and the mouse and the cytometry facility cores at Curie Institute., Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), PSL Research University (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), and Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Cancer Research, Chromosomal Proteins, Non-Histone, medicine.medical_treatment, T-Lymphocytes, [SDV]Life Sciences [q-bio], SMARCB1, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, single-cell RNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Immune system, endogenous retrovirus, medicine, Animals, Humans, tumor immunology, AT/RT, rhabdoid tumor, Immunogenicity, T-cell receptor, Nuclear Proteins, Cell Biology, Immunotherapy, Chromatin Assembly and Disassembly, Pediatric cancer, Immunohistochemistry, SWI/SNF, 3. Good health, Chromatin, pediatric cancer, DNA-Binding Proteins, Mice, Inbred C57BL, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, immunotherapy, T cell receptor, CD8, Transcription Factors
Abstract: International audience; Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation.
Published: 2019

44. Targeting CCR5 trafficking to inhibit HIV-1 infection

Author: Anne Brelot, Elaine Del Nery, Yuko Fukata, Gaelle Boncompain, Masaki Fukata, Isabelle Staropoli, Sarah Tessier, Floriane Herit, Pierre Gestraud, Florence Niedergang, Franck Perez, Aurianne Lescure, Université Paris sciences et lettres (PSL), Dynamique de l’organisation intra-cellulaire, Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de criblage à haute teneur en biophénic [Institut Curie] (Biophenics High-Content Screening Laboratory), Institut Curie [Paris]-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénie Virale - Viral Pathogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Membrane Physiology, Department of Molecular and Cellular Physiology [Okazaki], National Institute for Physiological Sciences-National Institutes of Natural Sciences [Tokyo] (NINS), We acknowledge the Cell and Tissue Imaging Facility (PICT-IBiSA), Institut Curie, a member of the French National Research Infrastructure, France-BioImaging (ANR10-INBS-04). This work was supported by grants from CNRS, INSERM, Université Paris Descartes, Agence Nationale de la Recherche (2011 BSV3 025 02), and Agence Nationale de Recherches sur le Sida et les Hépatites (ANRS, AO2012-2) to A.B., F.P., and F.N., and Fondation pour la Recherche Médicale (FRM DEQ20130326518) to F.N. This work has received support under the 'Investissements d’Avenir' program launched by the French government and implemented by ANR with the references ANR-10-LABX-62-IBEID and ANR-10-IDEX-0001-02 PSL, ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), PSL Research University (PSL), Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-PSL Research University Paris, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénie Virale, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-INBS-04-01/10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), ANR-10-IDEX-0001-02/10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: CCR1, Receptors, CXCR4, Receptors, CCR5, Cell, Receptors, CCR1, HIV Infections, CXCR4, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Palmitoylation, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cell Line, Tumor, medicine, Humans, Amino Acid Sequence, 030212 general & internal medicine, Receptor, Research Articles, Secretory pathway, 030304 developmental biology, 0303 health sciences, Secretory Pathway, Multidisciplinary, Chemistry, Macrophages, HEK 293 cells, SciAdv r-articles, virus diseases, Cell Biology, respiratory system, 3. Good health, Transport protein, Cell biology, Protein Transport, HEK293 Cells, medicine.anatomical_structure, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, human activities, HeLa Cells, Research Article
Abstract: The diversity of secretory routes enabled the identification of specific inhibitors of CCR5 transport and HIV-1 infection., Using a cell-based assay monitoring differential protein transport in the secretory pathway coupled to high-content screening, we have identified three molecules that specifically reduce the delivery of the major co-receptor for HIV-1, CCR5, to the plasma membrane. They have no effect on the closely related receptors CCR1 and CXCR4. These molecules are also potent in primary macrophages as they markedly decrease HIV entry. At the molecular level, two of these molecules inhibit the critical palmitoylation of CCR5 and thereby block CCR5 in the early secretory pathway. Our results open a clear therapeutics avenue based on trafficking control and demonstrate that preventing HIV infection can be performed at the level of its receptor delivery.
Published: 2019

45. Using a new diagnostic tool to predict lymph node metastasis in advanced epithelial ovarian cancer leads to simple lymphadenectomy decision rules: A multicentre study from the FRANCOGYN group

Author: Arnaud Fauconnier, Matthieu Mezzadri, Sofiane Bendifallah, Jean Louis Benifla, Roman Rouzier, Yohan Kerbage, Vincent Lavoué, Xavier Paoletti, Geoffroy Canlorbe, Camille Mimoun, Charles Coutant, Cyrille Huchon, Lobna Ouldamer, Adrien Crestani, Cyril Touboul, Thomas Gaillard, Yohann Dabi, Alexandre Bricou, Lise Lecointre, Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de gynécologie et obstétrique [Hopital Lariboisière - Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Département d'Oncologie Chirurgicale [Institut Curie], Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de gynécologie-obstétrique [Hôpital Jean Verdier], Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Service de gynécologie et obstétrique [Créteil], CHI Créteil, Service de Gynécologie-Obstétrique, Maternité, Chirurgie Gynécologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique de Gynécologie [Lille] (Hôpital Jeanne de Flandre), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes], Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département de Gynécologie-Obstétrique [CHU Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de gynécologie et obstétrique [CHI Poissy-Saint Germain], CHI Poissy-Saint-Germain, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Mines Paris - PSL (École nationale supérieure des mines de Paris), Service de Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon], and HAL UVSQ, Équipe
Subjects: Oncology, Epidemiology, medicine.medical_treatment, Cancer Treatment, Pelvic Lymphadenectomy, Lymph node metastasis, Carcinoma, Ovarian Epithelial, Logistic regression, Surgical planning, Metastasis, Mathematical and Statistical Techniques, 0302 clinical medicine, Positron Emission Tomography Computed Tomography, Basic Cancer Research, Medicine and Health Sciences, Blood and Lymphatic System Procedures, Medicine, Ovarian Neoplasms, 0303 health sciences, Multidisciplinary, Cancer Risk Factors, Statistics, Cytoreduction Surgical Procedures, Middle Aged, 3. Good health, Surgical Oncology, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Physical Sciences, Cohort, Female, France, Anatomy, Research Article, Clinical Oncology, medicine.medical_specialty, Science, Clinical Decision-Making, Surgical and Invasive Medical Procedures, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Research and Analysis Methods, Lymphatic System, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, Statistical Methods, Aged, Retrospective Studies, 030304 developmental biology, Internet, business.industry, Biology and Life Sciences, Lymphadenectomy, Decision rule, medicine.disease, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Logistic Models, Medical Risk Factors, Lymph Node Excision, Lymph Nodes, Clinical Medicine, business, Ovarian cancer, Mathematics, Forecasting
Abstract: Objective The aim of this study was to develop a new diagnostic tool to predict lymph node metastasis (LNM) in patients with advanced epithelial ovarian cancer undergoing primary cytoreductive surgery. Materials and method The FRANCOGYN group’s multicenter retrospective ovarian cancer cohort furnished the patient population on which we developed a logistic regression model. The prediction model equation enabled us to create LNM risk groups with simple lymphadenectomy decision rules associated with a user-friendly free interactive web application called shinyLNM. Results 277 patients from the FRANCOGYN cohort were included; 115 with no LNM and 162 with LNM. Three variables were independently and significantly (p Conclusion This new tool may prove useful for improving surgical planning and provide useful information for patients.
Published: 2021

46. Independent Component Analysis for Unraveling the Complexity of Cancer Omics Datasets

Author: Alexander N. Gorban, Askhat Molkenov, Ulykbek Kairov, Andrei Zinovyev, Laura Cantini, Nicolas Sompairac, Zhaxybay Zhumadilov, Urszula Czerwinska, Petr V. Nazarov, Anne Biton, François Radvanyi, Emmanuel Barillot, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Luxembourg Institute of Health (LIH), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Nazarbayev University [Kazakhstan], Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Leicester, Lobachevsky State University [Nizhni Novgorod], This work was partially supported by the grant research projects 'Pan-cancer deconvolution of omics data using Independent Component Analysis' (IRN: AP05135430) and 'Investigation of esophageal cancer tissue gene expression derived from Kazakhstan patients by next-generation sequencing technology' (IRN: AP05134722) of the Ministry of Education and Science of the Republic of Kazakhstan, by the Ministry of Science and Higher Education of the Russian Federation (Project No. 14.Y26.31.0022), the European Union’s Horizon 2020 program (grant No. 826121, iPC project), by the European IMI IMMUCAN project, and by Luxembourg National Research Fund (C17/BM/11664971/DEMICS)., PSL Research University (PSL), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Databases, Factual, Computer science, dimension reduction, data analysis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, computer.software_genre, Data type, Catalysis, Matrix decomposition, Non-negative matrix factorization, Inorganic Chemistry, Machine Learning, lcsh:Chemistry, 03 medical and health sciences, Matrix (mathematics), 0302 clinical medicine, Neoplasms, Humans, cancer, Physical and Theoretical Chemistry, Molecular Biology, lcsh:QH301-705.5, data integration, Spectroscopy, Data Curation, 030304 developmental biology, 0303 health sciences, Principal Component Analysis, Dimensionality reduction, Organic Chemistry, Computational Biology, General Medicine, Independent component analysis, Magnetic Resonance Imaging, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Computer Science Applications, omics data, lcsh:Biology (General), lcsh:QD1-999, independent component analysis, Principal component analysis, Data mining, computer, 030217 neurology & neurosurgery, Algorithms, Data integration
Abstract: Independent component analysis (ICA) is a matrix factorization approach where the signalscaptured by each individual matrix factors are optimized to become as mutually independent aspossible. Initially suggested for solving source blind separation problems in various fields, ICA wasshown to be successful in analyzing functional magnetic resonance imaging (fMRI) and other typesof biomedical data. In the last twenty years, ICA became a part of the standard machine learningtoolbox, together with other matrix factorization methods such as principal component analysis (PCA)and non-negative matrix factorization (NMF). Here, we review a number of recent works where ICAwas shown to be a useful tool for unraveling the complexity of cancer biology from the analysis ofdifferent types of omics data, mainly collected for tumoral samples. Such works highlight the useof ICA in dimensionality reduction, deconvolution, data pre-processing, meta-analysis, and othersapplied to dierent data types (transcriptome, methylome, proteome, single-cell data). We particularlyfocus on the technical aspects of ICA application in omics studies such as using different protocols,determining the optimal number of components, assessing and improving reproducibility of the ICAresults, and comparison with other popular matrix factorization techniques. We discuss the emergingICA applications to the integrative analysis of multi-level omics datasets and introduce a conceptualview on ICA as a tool for defining functional subsystems of a complex biological system and theirinteractions under various conditions. Our review is accompanied by a Jupyter notebook whichillustrates the discussed concepts and provides a practical tool for applying ICA to the analysis ofcancer omics datasets.
Published: 2019

47. ipcwswitch: An R package for inverse probability of censoring weighting with an application to switches in clinical trials

Author: Aurélien Latouche, Sylvie Chevret, Christophe Le Tourneau, Nathalie Grafféo, Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), Université Paris Diderot - Paris 7 (UPD7)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), CEDRIC. Méthodes statistiques de data-mining et apprentissage (CEDRIC - MSDMA), Centre d'études et de recherche en informatique et communications (CEDRIC), Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Curie [Paris], Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut national du cancer [Boulogne] (INCA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-CHU Saint Louis [APHP], and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, Computer science, media_common.quotation_subject, Health Informatics, law.invention, 03 medical and health sciences, 0302 clinical medicine, [STAT.AP] Statistics [stat]/Applications [stat.AP], Randomized controlled trial, law, Neoplasms, Covariate, Statistics, Humans, Survival analysis, ComputingMilieux_MISCELLANEOUS, media_common, Randomized Controlled Trials as Topic, Selection bias, [STAT.AP]Statistics [stat]/Applications [stat.AP], Inverse probability weighting, Survival Analysis, Computer Science Applications, Weighting, 030104 developmental biology, Inverse probability, Censoring (clinical trials), Data Interpretation, Statistical, 030217 neurology & neurosurgery, Software
Abstract: In randomized clinical trials (RCT), the analysis is based on the intent-to-treat principle to avoid any selection bias in the constitution of groups. However, estimates of overall survival can be biased when significant crossover occurs because the separation of randomized groups is lost. To handle these switches, the inverse probability of censoring weighting (IPCW) method has been proposed; however, it is still poorly used in RCT, notably because of its complex implementation. In particular, for time-to-event outcomes, it can be difficult to format data, especially when time-dependent covariates have to be managed, with different measurement times between patients. This paper aims to present the R package ipcwswitch with some guidance for the analysis of the treatment effect on survival in a hypothetical setting where all patients would have continued to take the randomization treatment. After a brief recall of the key principles of the IPCW method, each step of the implementation is described using a toy example. The guidelines are illustrated in a case study that aimed at evaluating the benefit of therapy based on tumour molecular profiling for advanced cancers, SHIVA01.
Published: 2019

48. Efficacy of molecularly targeted agents given in the randomised trial SHIVA01 according to the ESMO Scale for Clinical Actionability of molecular Targets

Author: Gaëlle Pierron, Sophie Vacher, Aurelie Moreira, M.P. Sablin, Céline Callens, Francesco Ricci, Delphine Loirat, Virginie Bernard, Julien Masliah-Planchon, N. Servant, Samia Melaabi, C. Le Tourneau, Maxime Frelaut, A. Vincent Salomon, Edith Borcoman, Ségolène Hescot, Ivan Bièche, O. Trabelsi-Grati, David Gentien, Charlotte Lecerf, P. Tresca, Nouritza Torossian, Maud Kamal, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Statistical difference, Medical Oncology, Targeted therapy, 0302 clinical medicine, Molecular Targeted Therapy, Precision Medicine, Drug Approval, health care economics and organizations, Societies, Medical, Randomized Controlled Trials as Topic, Aged, 80 and over, Middle Aged, Prognosis, 3. Good health, Treatment Outcome, Research Design, 030220 oncology & carcinogenesis, Evidence-Based Practice, Female, France, Algorithms, Adult, medicine.medical_specialty, Standard of care, Adolescent, education, Antineoplastic Agents, Proof of Concept Study, Disease-Free Survival, 03 medical and health sciences, Young Adult, Clinical Trials, Phase II as Topic, health services administration, Internal medicine, medicine, Overall survival, Humans, In patient, Aged, Retrospective Studies, business.industry, Precision medicine, 030104 developmental biology, Molecular targets, Conventional chemotherapy, business
Abstract: Background A randomised trial SHIVA01 compared the efficacy of matched molecularly targeted therapy outside their indications based on a prespecified treatment algorithm versus conventional chemotherapy in patients with metastatic solid tumours who had failed standard of care. No statistical difference was reported between the two groups in terms of progression-free survival (PFS), challenging treatment algorithm. The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) recently defined criteria to prioritise molecular alterations (MAs) to select anticancer drugs. We aimed to retrospectively evaluate the efficacy of matched molecularly targeted agents (MTAs) given in SHIVA01 according to ESCAT tiers. Patients and methods MAs used in SHIVA01 were retrospectively classified into ESCAT tiers, and PFS and overall survival (OS) were compared using log-rank tests. Results One hundred fifty-three patients were treated with matched MTAs in SHIVA01. MAs used to allocate MTAs were classified into tiers II, IIIA, IIIB and IVA according to the ESCAT. Median PFS was 2.0 months in tier II, 3.1 in tier IIIA, 1.7 in tier IIIB and 3.2 in tier IVA (p = 0.13). Median OS in tier IIIB was worse than that in tiers II, IIIA and IVA (6.3 months versus 11.7, 11.2 and 12.1, p = 0.002). Conclusions Most MAs used to allocate therapy in SHIVA01 were shown to improve outcomes in other tumour types (tier IIIA). Worst outcome was observed in patients treated based on another type of alteration than the one reported to improve outcomes (tier IIIB), highlighting the crucial impact of the type of the alterations beyond the gene and the signalling pathway.
Published: 2019

49. An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma

Author: Alessandro Raso, Alain Eychène, Antoine Forget, Michael D. Taylor, Morgane Morabito, Magalie Larcher, Franck Bourdeaut, Florence M.G. Cavalli, Liliana Mirabal-Ortega, Olivier Delattre, Chloe Foray, Abel Debalkew, François Doz, Julien Masliah-Planchon, Sophie Leboucher, Celio Pouponnot, Alexandra Garancher, Mamy Andrianteranagna, Stéphanie Puget, Sabine Druillennec, Olivier Ayrault, Department of Anatomy and Cell Biology [Montréal], McGill University, Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), PSL Research University (PSL), Institut Curie, Université Paris Sud Orsay, Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Signalisation cellulaire et neurobiologie (SNC), McGill University = Université McGill [Montréal, Canada], Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Institut Curie [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Cerebellum, Medicine (General), medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Apoptosis, Smad2 Protein, QH426-470, 0302 clinical medicine, Transforming Growth Factor beta, Phosphorylation, Receptor, Cancer, Inhibin-beta Subunits, activin, Articles, 3. Good health, Tumor Burden, Gene Expression Regulation, Neoplastic, Autocrine Communication, medicine.anatomical_structure, TGFbeta, Quinolines, Molecular Medicine, Female, Signal Transduction, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, medulloblastoma, Article, TGFbeta Subject Category Cancer, Transforming Growth Factor beta1, 03 medical and health sciences, R5-920, Transforming Growth Factor beta3, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cell Line, Tumor, medicine, Genetics, Galunisertib, Animals, Humans, Smad3 Protein, Autocrine signalling, Cerebellar Neoplasms, Cell Proliferation, Medulloblastoma, Chemotherapy, business.industry, Mechanism (biology), Membrane Proteins, medicine.disease, Xenograft Model Antitumor Assays, Radiation therapy, 030104 developmental biology, Cancer research, Pyrazoles, business, 030217 neurology & neurosurgery, Smad2, Smad3
Abstract: International audience; Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFb/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFb/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.
Published: 2019

50. DropLasso: A robust variant of Lasso for single cell RNA-seq data

Author: Khalfaoui, Beyrem, Vert, Jean-Philippe, Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Mathématiques et Applications - ENS Paris (DMA), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genomics (q-bio.GN), FOS: Computer and information sciences, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Statistics - Machine Learning, Computer Vision and Pattern Recognition (cs.CV), FOS: Biological sciences, Computer Science - Computer Vision and Pattern Recognition, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Quantitative Biology - Genomics, Machine Learning (stat.ML), Quantitative Biology - Quantitative Methods, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Quantitative Methods (q-bio.QM)
Abstract: Single-cell RNA sequencing (scRNA-seq) is a fast growing approach to measure the genome-wide transcriptome of many individual cells in parallel, but results in noisy data with many dropout events. Existing methods to learn molecular signatures from bulk transcriptomic data may therefore not be adapted to scRNA-seq data, in order to automatically classify individual cells into predefined classes. We propose a new method called DropLasso to learn a molecular signature from scRNA-seq data. DropLasso extends the dropout regularisation technique, popular in neural network training, to esti- mate sparse linear models. It is well adapted to data corrupted by dropout noise, such as scRNA-seq data, and we clarify how it relates to elastic net regularisation. We provide promising results on simulated and real scRNA-seq data, suggesting that DropLasso may be better adapted than standard regularisa- tions to infer molecular signatures from scRNA-seq data.
Published: 2019

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

153 results on '"Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources