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19 results on '"Fondation Synergie Lyon Cancer [Lyon]"'

1. Genetic analysis of lung cancer and the germline impact on somatic mutation burden

Author: Gabriel, AAG, Atkins, JR, Penha, RCC, Smith-Byrne, K, Gaborieau, V, Voegele, C, Abedi-Ardekani, B, Milojevic, M, Olaso, R, Meyer, V, Boland, A, Deleuze, JF, Zaridze, D, Mukeriya, A, Swiatkowska, B, Janout, V, Schejbalová, M, Mates, D, Stojšić, J, Ognjanovic, M, consortium, ILCCO, Witte, JS, Rashkin, SR, Kachuri, L, Hung, RJ, Kar, S, Brennan, P, Sertier, A-S, Ferrari, A, Viari, A, Johansson, M, Amos, CI, Foll, M, McKay, JD, 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), University of Oxford, Université Paris-Saclay, N.N. Blokhin Russian Cancer Research Center, Nofer Institute of Occupational Medicine (NIOM), Palacky University Olomouc, Charles University [Prague] (CU), National Institute of Public Health [Romania] (INSP), University Clinical Centre of Serbia, International Organisation for Cancer Prevention and Research, University of California [San Francisco] (UC San Francisco), University of California (UC), St Jude Children's Research Hospital, Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada, University of Bristol [Bristol], Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), 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)-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)-Inria Lyon, Institut National de Recherche en Informatique et en Automatique (Inria), Baylor College of Medicine (BCM), and Baylor University
Subjects: Cancer Research, Germ Cells, Lung Neoplasms, Oncology, [SDV]Life Sciences [q-bio], Mutation, Humans, Genetic Predisposition to Disease, ICEP, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract: Background Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. Methods To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. Results The GWAx–GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P Conclusions This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.
Published: 2022
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2. Gene signature of circulating platelet-bound neutrophils is associated with poor prognosis in cancer patients

Author: Pacôme Lecot, Maude Ardin, Sébastien Dussurgey, Vincent Alcazer, Lyvia Moudombi, Manuela Pereira Abrantes, Margaux Hubert, Aurélie Swalduz, Hector Hernandez‐Vargas, Alain Viari, Christophe Caux, Marie‐Cécile Michallet, 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), Centre Léon Bérard [Lyon], SFR Biosciences, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Plateforme de Bioinformatique Gilles Thomas [Lyon], Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon]-Centre Léon Bérard [Lyon], ANR-17-CONV-0002,PLASCAN,Institut François Rabelais pour la recherche multidisciplinaire sur le cancer(2017), and ANR-17-RHUS-0008,MYPROBE,Molecumar assaYs to PRedict Outcome in early Breast cancER(2017)
Subjects: Blood Platelets, Cancer Research, Oncology, low-density-neutrophils, Neutrophils, [SDV]Life Sciences [q-bio], Neoplasms, platelets, cancer, neutrophil-platelet aggregates, Humans, Flow Cytometry, Prognosis
Abstract: International audience; Beyond their critical role in hemostasis, platelets physically interact with neutrophils to form neutrophil-platelet aggregates (NPAs), enhancing neutrophil effector functions during inflammation. NPAs may also promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. Using ImageStreamX (ISX) imaging flow cytometer, we were not only allowed able to detect CD15+ CD14- CD36+ ITGA2B+ NPAs in both healthy donors' (HDs) and cancer patients' bloods, but we also showed that NPAs result from the binding of platelets preferentially to low-density neutrophils (LDNs) as opposed to normal-density neutrophils (NDNs). By reanalyzing two independent public scRNAseq data of whole blood leukocytes from cancer patients and HDs, we could identify a subset of neutrophils with high platelet gene expression that may correspond to NPAs. Moreover, we showed that cancer patients' derived NPAs possessed a distinct molecular signature compared to the other neutrophil subsets, independently of platelet genes. Gene ontology (GO) term enrichment analysis of this NPAs-associated neutrophil transcriptomic signature revealed a significant enrichment of neutrophil degranulation, chemotaxis and trans-endothelial migration GO terms. Lastly, using The Cancer Genome Atlas (TCGA), we could show by multivariate Cox analysis that the NPAs-associated neutrophil transcriptomic signature was associated with a worse patient prognosis in several cancer types. These results suggest that neutrophils from NPAs are systemically primed by platelets empowering them with cancer progression capacities once at tumor site. NPAs may therefore hold clinical utility as novel noninvasive blood prognostic biomarker in cancer patients with solid tumors.
Published: 2022
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3. Comprehensive Genome Profiling in Patients With Metastatic Non-Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Author: Boyault, Sandrine, Attignon, Valery, Soubeyran, Isabelle, Morel, Alain, Tran-Dien, Alicia, Jacquet, Alexandra, Dall'Olio, Filippo Gustavo, Jimenez, Marta, Soria, Jean-Charles, Besse, Benjamin, Barlesi, Fabrice, Tomasini, Pascale, Karimi, Maryam, Michiels, Stefan, Raimbourg, Judith, Daniel, Catherine, Janicot, Henri, Madroszyk, Anne, Audigier-Valette, Clarisse, Quoix, Elisabeth, Mazieres, Julien, Moro-Sibilot, Denis, Dansin, Eric, Molinier, Olivier, Morel, Hugues, Pichon, Eric, Cortot, Alexis, Otto, Josiane, Chomy, Francois, Souquet, Pierre-Jean, Cloarec, Nicolas, Giroux-Leprieur, Etienne, Bieche, Ivan, Lacroix, Ludovic, Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Multidisciplinary Oncology and Therapeutic Innovations Unit, Hôpital Nord [CHU - APHM], Tarbiat Modares University [Tehran], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), 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, Institut Curie [Paris], Service de Pneumologie [CHU Clermont-Ferrand], Pôle RHEUNNIRS [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, CHU Strasbourg, Service de pneumologie [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU de Grenoble-Alpes, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Hospitalier Le Mans (CH Le Mans), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Henri Duffaut (Avignon), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, and Département de biologie et pathologie médicales [Gustave Roussy]
Subjects: ErbB Receptors, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, [SDV]Life Sciences [q-bio], Antineoplastic Combined Chemotherapy Protocols, Mutation, Humans, Receptor Protein-Tyrosine Kinases, Precision Medicine, B7-H1 Antigen
Abstract: International audience; Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods: SAFIR02-Lung was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6-2.9] with TT versus 2.7 months (1.6-4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7-1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62-1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) >= 1%, (n = 29; HR, 0.29; 95% CI, 0.11-0.75) as compared with PD-L1 < 1% (n = 31; HR, 0.71; 95% CI, 0.31-1.60; P-interaction = 0.036). Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 >= 1 patients.
Published: 2022
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4. Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming

Author: Carras, Sylvain, Chartoire, Dimitri, Mareschal, Sylvain, Heiblig, Maël, Marçais, Antoine, Robinot, Rémy, Urb, Mirjam, Pommier, Roxane, Julia, Edith, Chebel, Amel, Verney, Aurélie, Bertheau, Charlotte, Bardel, Emilie, Fezelot, Caroline, Courtois, Lucien, Lours, Camille, Bouska, Alyssa, Sharma, Sunandini, Lefebvre, Christine, Rouault, Jean-Pierre, Sibon, David, Ferrari, Anthony, Iqbal, Javeed, de Leval, Laurence, Gaulard, Philippe, Traverse-Glehen, Alexandra, Sujobert, Pierre, Blery, Mathieu, Salles, Gilles, Walzer, Thierry, Bachy, Emmanuel, Genestier, Laurent, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), 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), Activation et transduction du signal dans les lymphocytes - Lymphocyte activation and signaling (LYACTS), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], University of Nebraska Medical Center, University of Nebraska System, Centre Hospitalier Universitaire [Grenoble] (CHU), 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), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Lausanne (UNIL), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, CHU Henri Mondor, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Innate Pharma, École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), 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)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), 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), Fondation Synergie Lyon Cancer [Lyon], Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), and CHU Henri Mondor [Créteil]
Subjects: [SDV]Life Sciences [q-bio], Immunology, T cells, hemic and immune systems, Lymphomas, Hematology, T cell receptor
Abstract: International audience; Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.
Published: 2021
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5. The circular RNome of primary breast cancer

Author: Steven Van Laere, Colin A. Purdie, John A. Foekens, Gaëten MacGrogan, Marcel Smid, Andrew Futreal, Vanja de Weerd, Paul N. Span, Marc J. van de Vijver, Jorunn E. Eyfjord, Serena Nik-Zainal, F. Germán Rodríguez-González, Roberto Salgado, Peter T. Simpson, Christine Desmedt, Wendy J. C. Prager-van der Smissen, Fred C.G.J. Sweep, Tari A. King, Adam Butler, Michael R. Stratton, Carlos Caldas, Gert Van den Eynden, Sunil R. Lakhani, Saskia M. Wilting, Alastair M. Thompson, Angelo Paradiso, John W.M. Martens, Anne Vincent-Salomon, Johan Staaf, Anne van Galen, Sancha Martin, Hendrik G. Stunnenberg, Annegien Broeks, Andrea L. Richardson, Anne Lise Børresen-Dale, Helen Davies, Michelle van der Vlugt-Daane, Katharina Uhr, Stian Knappskog, Alain Viari, Anieta M. Sieuwerts, Medical Oncology, Smid, Marcel [0000-0003-0605-1901], Apollo - University of Cambridge Repository, Pathology, CCA - Cancer biology and immunology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Dana-Farber Cancer Institute [Boston], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Institut Bergonié [Bordeaux], UNICANCER, Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Translational Cancer Research Unit [Antwerp], Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], Radboud University Medical Center [Nijmegen], University of Southern Queensland (USQ), University of Antwerp (UA), Istituto Tumori 'Giovanni Paolo II' [Bari], University of Iceland [Reykjavik], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, 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), The University of Texas M.D. Anderson Cancer Center [Houston], University of Bergen (UiB), Haukeland University Hospital, Memorial Sloane Kettering Cancer Center [New York], Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institute for Cancer Research [Oslo], Oslo University Hospital [Oslo], Fondation Synergie Lyon Cancer [Lyon], Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: Génétique clinique, Proliferation index, [SDV]Life Sciences [q-bio], Transcriptome, Exon, Breast cancer, 0302 clinical medicine, Brjóstakrabbamein, MUTATIONAL PROCESSES, Genetics (clinical), Genetics & Heredity, 0303 health sciences, Gene knockdown, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], ABUNDANT, CREB-Binding Protein, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, GENOME, Chemistry, Lymphatic Metastasis, RNA splicing, MCF-7 Cells, Female, Engineering sciences. Technology, Biologie, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Breast Neoplasms, Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, REVEALS, Biomarkers, Tumor, Genetics, medicine, Erfðafræði, Humans, TAMOXIFEN, Molecular Biology, Gene, SIGNATURES, 030304 developmental biology, Science & Technology, LANDSCAPE, Research, MICRORNA, Cancer, RNA, Circular, medicine.disease, DNA-rannsóknir, GENE, RNAs, Repressor Proteins, Biotechnology & Applied Microbiology, Cancer research, RNA, Human medicine, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: Publisher's version (útgefin grein), Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R < 0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer., We thank the Erasmus MC Cancer Computational Biology Center for giving access to their IT infrastructure and the software that was used for the computations and data analysis in this study. We thank Sandra Albassam for her help with the first versions of the script to identify circular regions. We thank Maurice P.H.M. Jansen, Jean C. Helmijr, Inge de Kruijff, and Manouk K. Bos for their help in evaluating plasma samples that were gathered in the EU-FP7 CareMore (nr 601760) project. We thank for technical support Miriam Ragle Aure and Anita Langerød of the Oslo University Hospital, Norway; Ewan Birney of the European Bioinformatics Institute, UK; and Stefania Tommasi of the IRCCS Istituto Tumori “Giovanni Paolo II,” Bari, Italy. We thank the Oslo Breast Cancer Research Consortium (OSBREAC), Norway (https://www.ous-research.no/home/kgjebsen/home/14105) for contributing patient samples and Sabine Linn and Marleen Kok of The Netherlands Cancer Institute for contributing samples for the AI cohort. Finally, we thank all members of the ICGC Breast Cancer Working Group. This work has been funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (a European research project funded by the European Community’s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006) and the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z). F.G.R.-G. and S.M. were funded by BASIS. J.A.F. was funded through an ERC Advanced Grant (ERC-2012-AdG-322737) and ERC Proof-of-Concept Grant (ERC-2017-PoC-767854). K.U. was funded by the Daniel den Hoed Foundation. S.N.-Z. is a Wellcome Beit Fellow and personally funded by a Wellcome Trust Intermediate Fellowship (WT100183MA). A.L.R. is partially supported by the Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer (NIH/NCI 5 P50 CA16 8504-02). A.M.S. was supported by Cancer Genomics Netherlands (CGC.nl) through a grant from the Netherlands Organization of Scientific research (NWO). M. Smid was supported by the EU-FP7-DDR response project. C.D. was supported by a grant from the Breast Cancer Research Foundation. J.E. was funded by The Icelandic Centre for Research (RANNIS).
Published: 2019
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6. Apport et défis des Big Data en cancérologie

Author: Jean-Philippe Foy, Alain Puisieux, Pierre Saintigny, Anthony Ferrari, Philippe A. Cassier, Alain Viari, 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), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Baobab, Département PEGASE [LBBE] (PEGASE), 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)-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)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), 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), and Synergie Lyon Cancer [Lyon]
Subjects: 0301 basic medicine, Cancer Research, Technological revolution, business.industry, Emerging technologies, Computer science, [SDV]Life Sciences [q-bio], Big data, Hematology, General Medicine, Precision medicine, Data science, 03 medical and health sciences, 030104 developmental biology, Oncology, Radiology, Nuclear Medicine and imaging, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business
Abstract: International audience; Depuis le premier séquençage du génome humain en 2001, le développement de nouvelles technologies à haut débit, ainsi que la diminution considérable du coût du séquençage ont permis des avancées importantes en oncologie. La caractérisation moléculaire des cancers a notamment permis d’identifier des anomalies oncogéniques clés au cours du processus tumoral, permettant le développement de stratégies thérapeutiques personnalisées. Cependant, la quantité d’information considérable ainsi générée a créé de nouveaux défis à relever comme le stockage, le traitement ou encore l’exploitation de l’information. Dans cet article, nous décrivons l’apport et les défis représentés par les Big Data en cancérologie.
Published: 2017
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7. Prediction of Breast Cancer Treatment-Induced Fatigue by Machine Learning Using Genome-Wide Association Data

Author: Paul Cottu, Anne-Laure Martin, Anne Boland, Cécile Charles, Jung Hun Oh, Marina Rousseau, Ines Vaz-Luis, Gwenn Menvielle, Joseph O. Deasy, Stefan Michiels, Céline Besse, Emilie Thomas, Jean-François Deleuze, Olivier Tredan, Patricia A. Ganz, Sandrine Boyault, Sibille Everhard, Fabrice Andre, Antonio Di Meglio, Ann H. Partridge, Agnès Dumas, Christelle Levy, Sangkyu Lee, Memorial Sloan Kettering Cancer Center (MSKCC), Institut Gustave Roussy (IGR), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, 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, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Léon Bérard [Lyon], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Fondation Synergie Lyon Cancer [Lyon], Institut Curie [Paris], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), UNICANCER, University of California [Los Angeles] (UCLA), University of California (UC), Dana-Farber Cancer Institute [Boston], Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Synergie Lyon Cancer [Lyon], and Gestionnaire, Hal Sorbonne Université
Subjects: Cancer Research, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Genome-wide association study, Machine learning, computer.software_genre, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Clinical endpoint, 030304 developmental biology, 0303 health sciences, Surrogate endpoint, business.industry, Cancer, medicine.disease, [SDV] Life Sciences [q-bio], Oncology, Quartile, 030220 oncology & carcinogenesis, Anxiety, Artificial intelligence, medicine.symptom, business, computer
Abstract: Background We aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data. Methods We accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic (P Results Statistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association (P Conclusions Genomic analyses in this large cohort of breast cancer survivors suggest a possible genetic role for severe Cognitive Fatigue that warrants further exploration.
Published: 2019
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8. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

Author: F. Le Calvez-Kelm, John K. Field, Nicolas Girard, Ernst-Jan M. Speel, Marie Brevet, Lynnette Fernandez-Cuesta, Jean-François Deleuze, Nicolas Lemaitre, Noémie Leblay, Sandrine Boyault, Marius Lund-Iversen, Gabriella Sozzi, Véronique Hofman, Sylvie Lantuejoul, Lucia Anna Muscarella, Paolo Graziano, Alex Soltermann, Matthieu Foll, Amelie Chabrier, Robert Olaso, A. Ferrari, Anne Boland, Paul Hofman, Luca Roz, Behnoush Abedi-Ardekani, Janine Altmüller, Tiffany M. Delhomme, Akram Ghantous, Christophe Caux, Jules L. Derks, Giuseppe Pelosi, Vincent Meyer, Anne-Marie C. Dingemans, Juan Sandoval, Jean-Michel Vignaud, Jelena Stojsic, Catherine Voegele, Geoffroy Durand, James D. McKay, Peter Nuernberg, Cyrille Cuenin, Nicolas Alcala, L. Moonen, Hector Hernandez-Vargas, Ugo Pastorino, Theo Giffon, O.T. Brustugun, L. Mangiante, Mauro Papotti, Philippe Lorimier, Anne-Claire Toffart, Prudence A. Russell, Aurélie A G Gabriel, Zdenko Herceg, A. S. Sertier, Joachim H. Clement, M. Milione, Joerg Saenger, Luka Brcic, Stéphanie Lacomme, V. Thomas de Montpreville, A. Viari, Marco Volante, Elisabeth Brambilla, Gavin M. Wright, Cécile Blanc-Fournier, David Hervás, N. Le Stang, H. Popper, Françoise Galateau-Sallé, Centre international de Recherche sur le Cancer (CIRC), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], 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), Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], School for Oncology and Developmental Biology [Maastricht] (GROW), Maastricht University [Maastricht]-Maastricht University Medical Centre (MUMC), 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 [2016-2019] (UGA [2016-2019]), Service de pneumologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Institute of Pathology and Molecular Pathology [Zurich], Department Hematology and Medical Oncology [Jena], Jena University Hospital [Jena], Central Clinic Bad Berka, Department of Molecular and Clinical Cancer Medicine [Liverpool], University of Liverpool, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), University of Melbourne, IRCCS Istituto Nazionale dei Tumori [Milano], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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), Oslo University Hospital [Oslo], Centre Chirurgical Marie Lannelongue (CCML), Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), University Hospital Graz, Clinical Center of Serbia (KCS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Università degli Studi di Milano = University of Milan (UNIMI), Università degli studi di Torino = University of Turin (UNITO), 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), Hospital Universitari i Politècnic La Fe, Synergie Lyon Cancer [Lyon], UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre chirurgical Marie Lannelongue, University of Milan, University of Turin, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Pulmonologie, RS: GROW - R2 - Basic and Translational Cancer Biology, MUMC+: MA Med Staf Spec Longziekten (9), and Pathologie
Subjects: 0301 basic medicine, Oncology, Male, Lung Neoplasms, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Datasets as Topic, 02 engineering and technology, Neuroendocrine tumors, Machine Learning, PATHWAY, Cancer genomics, lcsh:Science, Lung, Aged, 80 and over, Comparative Genomic Hybridization, Multidisciplinary, Intracellular Signaling Peptides and Proteins, Genomics, Middle Aged, 021001 nanoscience & nanotechnology, Prognosis, 3. Good health, Neuroendocrine Carcinomas, Survival Rate, medicine.anatomical_structure, Female, Non small cell, HEALTH, Technology Platforms, 0210 nano-technology, Adult, EXPRESSION, medicine.medical_specialty, Adolescent, Science, CELL LUNG-CANCER, Nerve Tissue Proteins, Carcinoid Tumor, DENDRITIC CELLS, General Biochemistry, Genetics and Molecular Biology, Article, Small-cell lung cancer, CLASSIFICATION, 03 medical and health sciences, Young Adult, Internal medicine, Overall survival, medicine, Carcinoma, Biomarkers, Tumor, Humans, Survival rate, Aged, Homeodomain Proteins, IDENTIFICATION, business.industry, MUTATIONS, Membrane Proteins, General Chemistry, medicine.disease, Small Cell Lung Carcinoma, 030104 developmental biology, DISCOVERY, Carcinoma, Large Cell, lcsh:Q, business, NEUROENDOCRINE TUMORS, Comparative genomic hybridization
Abstract: The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms., The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.
Published: 2019
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9. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer

Author: Jenny Valladeau-Guilemond, Elisa Gobbini, Christophe Sajous, Vincent Ollion, Céline Rodriguez, Olivier Tredan, Margaux Hubert, Isabelle Treilleux, Marc Dalod, Justine Berthet, Bertrand Dubois, Christophe Caux, Janice Kielbassa, Coline Couillault, Anne-Claire Doffin, Thien-Phong Vu Manh, Nathalie Bendriss-Vermare, 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Institut de Recherche en Mathématiques, Interactions et Applications (Labex_IRMIA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), SERM, INCA (PLBIO INCa_4508and PLBIO INCa_11155), ANRS, ARC, Ligue contre le Cancer (Régionale Auvergne-Rhône-Alpes et Saône-et-Loire, Comité de la Savoie), and la Région Rhône-Alpes Auvergne (IRICE), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Fondation Synergie Lyon Cancer [Lyon]
Subjects: 0301 basic medicine, Chemokine, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Immunology, Breast Neoplasms, Interferon Lambda, 03 medical and health sciences, 0302 clinical medicine, Immune system, Breast cancer, Interferon, Medicine, Cytotoxic T cell, Humans, biology, business.industry, General Medicine, Immunotherapy, Dendritic Cells, medicine.disease, Immunity, Innate, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, TLR3, biology.protein, Cancer research, Female, Interferons, business, Conventional Dendritic Cell, medicine.drug
Abstract: International audience; Dendritic cells play a key role in the orchestration of antitumor immune responses. The cDC1 (conventional dendritic cell 1) subset has been shown to be essential for antitumor responses and response to immunotherapy, but its precise role in humans is largely unexplored. Using a multidisciplinary approach, we demonstrate that human cDC1 play an important role in the antitumor immune response through their capacity to produce type III interferon (IFN-λ). By analyzing a large cohort of breast primary tumors and public transcriptomic datasets, we observed specific production of IFN-λ1 by cDC1. In addition, both IFN-λ1 and its receptor were associated with favorable patient outcomes. We show that IFN-III promotes a TH1 microenvironment through increased production of IL-12p70, IFN-γ, and cytotoxic lymphocyte–recruiting chemokines. Last, we showed that engagement of TLR3 is a therapeutic strategy to induce IFN-III production by tumor-associated cDC1. These data provide insight into potential IFN- or cDC1-targeting antitumor therapies.
Published: 2018
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10. Comprehensive molecular classification of localized prostate adenocarcinoma reveals a tumour subtype predictive of non-aggressive disease

Author: Gaëlle Fromont, Luc Multigner, Lucile Armenoult, Pascal Blanchet, Morgan Rouprêt, Geraldine Cancel-Tassin, A. Diedhiou, Laurent Doucet, A. de Reyniès, Georges Fournier, Aurélie Kamoun, X Leroy, Mira Ayadi, Eva Comperat, Jacques Irani, Arnauld Villers, Nabila Elarouci, Sandrine Boyault, Olivier Cussenot, Laurent Brureau, Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, CEREPP, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Ligue Contre le Cancer, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Ligue Nationale Contre le Cancer (LNCC), Fondation Synergie Lyon Cancer [Lyon], and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, Oncology, Male, medicine.medical_treatment, Datasets as Topic, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Epigenesis, Genetic, Prostate cancer, 0302 clinical medicine, Prostate, P-Chloroamphetamine, ComputingMilieux_MISCELLANEOUS, molecular classification, Prostatectomy, subtypes, Hematology, Middle Aged, prostate cancer, Subtyping, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Disease Progression, Biochemical recurrence, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, Risk Assessment, Disease-Free Survival, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Biomarkers, Tumor, genomics, Humans, Watchful Waiting, Aged, Retrospective Studies, Proportional hazards model, business.industry, Gene Expression Profiling, Patient Selection, Prostatic Neoplasms, biomarkers, DNA Methylation, Prostate-Specific Antigen, medicine.disease, 030104 developmental biology, Feasibility Studies, prognosis, business
Abstract: Background Management of localized prostate cancer (PCa) is a major clinical challenge since most of these cancers would not evolve but a majority of patients will still undergo a life-changing radical surgery. Molecular studies have shown that PCa can be classified according to their genomic alterations but none of the published PCa molecular classifications could identify a subtype corresponding to non-evolutive tumours. Materials and methods Multi-omics molecular profiling was carried out on post-radical prostatectomy material from a cohort of 130 patients with localized PCa. We used unsupervised classification techniques to build a comprehensive classification of prostate tumours based on three molecular levels: DNA copy number, DNA methylation, and mRNA expression. Merged data from our cohort and The Cancer Genome Atlas cohort were used to characterize the resulting tumour subtypes. We measured subtype-associated risks of biochemical relapse using Cox regression models and survival data from five cohorts including the two aforementioned. Results We describe three PCa molecular subtypes associated with specific molecular characteristics and different clinical outcomes. Particularly, one subtype was strongly associated with the absence of biochemical recurrence. We validated this finding on 746 samples from 5 distinct cohorts (P = 3.41 × 10−8, N = 746 tumour samples), and showed that our subtyping approach outperformed the most popular prognostic molecular signatures to accurately identify a subset of patients with a non-evolutive disease. We provide a set of 36 transcriptomic biomarkers to robustly identify this subtype of non-evolutive cases whose prevalence was estimated to 22% of all localized PCa tumours. Conclusion At least 20% of patients with localized PCa can be accurately predicted to have a non-evolutive disease on the basis of their molecular subtype. Those patients should not undergo immediate surgery and rather be placed under active surveillance.
Published: 2018
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11. A stemness-related ZEB1–MSRB3 axis governs cellular pliancy and breast cancer genome stability

Author: David G. Cox, Daniel Birnbaum, Qing Wang, Pascal Finetti, Frédéric Hollande, Emmanuelle Despras, François Bertucci, Emmanuelle Ruiz, Joël Lachuer, Christelle Chassot, Frédérique Fauvet, Pierre Saintigny, Roxane M. Pommier, Julie Caramel, Arnaud M. Vigneron, Anne Wierinckx, Nina Radosevic-Robin, Frédérique Penault-Llorca, Emmanuelle Charafe-Jauffret, Julien Wicinski, Emilie Thomas, Mojgan Devouassoux-Shisheboran, Stéphane Ansieau, Christiane Pinatel, Olivier Cabaud, Alain Puisieux, Anne-Pierre Morel, Jean-Luc Jauffret, Valérie Combaret, Jérôme Guitton, Caroline Moyret-Lalle, Agnès Tissier, Christophe Ginestier, Centre Léon Bérard [Lyon], 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service d'Anatomo-Pathologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Synergie Lyon Cancer [Lyon], Laboratoire de Génétique de la Radiosensibilité (LGR), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), clinique Phenicia, Service d'Oncologie Médicale, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), ProfileXpert, Université de Lyon, Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Melbourne, Cancérologie expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Arts et Métiers ParisTech d'Angers - Procédés Matériaux Durabilité ( LAMPA - PMD ), 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-Aix Marseille Université ( AMU ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Oncologie Moléculaire, Oncovirologie et Biothérapies, Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Laboratoire de Génétique de la Radiosensibilité ( LGR ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Laboratoire de Toxicologie ( ISPB ), Université de Lyon-Université de Lyon, Hunan Institute of Science and Technology, Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Centre Jean Perrin, CRLCC Jean Perrin, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Equipe 6, Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), equipe 2, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -labex DEVweCAN, Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ) -Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Synergie Lyon Cancer [Lyon], Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Genome instability, Pathology, Cellular differentiation, [SDV]Life Sciences [q-bio], Fluorescent Antibody Technique, medicine.disease_cause, Malignant transformation, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, Inbred NOD, Chromosome instability, Aged, 80 and over, Stem Cells, Cell Differentiation, General Medicine, Middle Aged, Flow Cytometry, 3. Good health, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Female, Stem cell, Adult, Chromatin Immunoprecipitation, medicine.medical_specialty, Adolescent, DNA damage, Immunoblotting, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, Genomic Instability, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Epithelial–mesenchymal transition, Mammary Glands, Human, Aged, Gene Expression Profiling, Carcinoma, Zinc Finger E-box-Binding Homeobox 1, Epithelial Cells, Sequence Analysis, DNA, 030104 developmental biology, Tissue Array Analysis, Methionine Sulfoxide Reductases, Cancer research, Tumor Suppressor Protein p53, Reactive Oxygen Species, Carcinogenesis, DNA Damage
Abstract: International audience; Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.
Published: 2017
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12. BCL2 mutations do not confer adverse prognosis in follicular lymphoma patients treated with rituximab

Author: Catherine Chassagne-Clément, Elizabeth Punnoose, Luc Xerri, Sarah Huet, Wayne J. Fairbrother, Kiran Mukhyala, Laurie Tonon, Edith Szafer-Glusman, Alain Viari, Pierre Sujobert, Gilles Salles, Pierre Feugier, Christopher R. Bolen, Bruno Tesson, Fabrice Jardin, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Genentech, Inc., Genentech, Inc. [San Francisco], Institut Carnot CALYM [Pierre-Benite], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Aix Marseille Université (AMU), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), 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)-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)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), 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), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Institut Carnot Lymphome (CALYM), Fondation Synergie Lyon Cancer [Lyon], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Follicular lymphoma, Antineoplastic Agents, Context (language use), medicine.disease_cause, Translocation, Genetic, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, medicine, Activation-induced (cytidine) deaminase, Humans, Prospective cohort study, Lymphoma, Follicular, Mutation, biology, business.industry, Hematology, Cytidine deaminase, Prognosis, medicine.disease, Lymphoma, Treatment Outcome, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Immunology, biology.protein, Female, Rituximab, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, medicine.drug
Abstract: International audience; BCL2 mutations have been suggested to confer an adverse prognosis to follicular lymphoma (FL) patients, but their prognostic value has not been assessed in patients treated with a rituximab-containing regimen. Here we evaluated the prognostic value of BCL2 mutations in a large prospective cohort of 252 patients with FL treated with immunochemotherapy in the PRIMA randomized trial. Using a DNA-targeted sequencing approach, we detected amino acid altering mutations in 135 patients (54%) and showed that these mutations were probably mediated by the over-activation of AICDA (activation-induced cytidine deaminase) in the context of the t(14;18) translocation. The BCL2 variants identified in PRIMA patients affected the BH1, BH2, and BH3 functional motifs at a lower frequency than the N-terminus and flexible loop domain, with mostly conservative aminoacid changes. With a median follow-up of 6.7 years, we did not observe any impact of BCL2 mutations either on overall survival or progression-free survival.
Published: 2017
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13. GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

Author: Xavier Pivot, Maria Rios, Anne Boland, Hugues Bourgeois, Véronique Trillet-Lenoir, Pierre Fumoleau, Elsa Curtit, Thomas Bachelot, Christelle Levy, Thierry Petit, Gilles Thomas, Iris Pauporté, Isabelle Tennevet, Jean-Marc Ferrero, Ariane Darut-Jouve, Delphine Bacq, Sandrine Lavau-Denes, Hélène Blanché, Marie-Christine Mathieu, Jean-Philippe Jacquin, Hervé Bonnefoi, Jean-Yves Pierga, Gilles Romieu, Jean-François Deleuze, Céline Faure-Mercier, David G. Cox, Céline Besse, Jérôme Meunier, David Assouline, Valérie Delecroix, Carole Tarpin, Mourad Sahbatou, Christelle Jouannaud, Patrick Soulié, Oana Cojocarasu, 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), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), 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 Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Institut Jean Godinot [Reims], Service d'Oncologie médicale [Clinique Victor Hugo], Clinique Victor Hugo, Centre Paul Strauss, CRLCC Paul Strauss, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut Daniel Hollard, Institut Gustave Roussy (IGR), Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, CHU Limoges, Clinique Drévon, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), 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), Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Pôle Mutualiste, Service Oncologie Médicale, Delft University of Technology (TU Delft), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Le Mans (CH Le Mans), Centre Hospitalier Régional d'Orléans (CHRO), Institut Curie [Paris], Institut National du Cancer, INCA, Fondation Jean Dausset CEPH, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Synergie Lyon Cancer [Lyon], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Fondation Synergie Lyon Cancer [Lyon]
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Receptor, ErbB-2, Estrogen receptor, Genome-wide association study, Locus (genetics), Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, HER2, Epidemiology, Biomarkers, Tumor, Medicine, Humans, GWAS, Genetic Predisposition to Disease, Receptor, Fibroblast Growth Factor, Type 2, skin and connective tissue diseases, Estrogen Receptor Status, breast, Randomized Controlled Trials as Topic, Gynecology, business.industry, association, medicine.disease, 3. Good health, 030104 developmental biology, Clinical Trials, Phase III as Topic, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Genome-Wide Association Study, Research Paper, estrogen receptor
Abstract: International audience; Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46x10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16x10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors.
Published: 2016
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14. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

Author: Stefania Tommasi, Johan Staaf, Ewan Birney, Steven Van Laere, Sunil R. Lakhani, Marcel Smid, Tari Ta King, Serena Nik-Zainal, Peter T. Simpson, Gert Van den Eynden, Andrea L. Richardson, Annegien Broeks, Adam A Butler, John A. Foekens, Alain Viari, Reno Debets, Gaëtan MacGrogan, Anne Lise Børresen-Dale, Colin A. Purdie, Mike M Stratton, Arie B. Brinkman, Hendrik G. Stunnenberg, Sancha Martin, Gilles Thomas, P. Andrew Futreal, Anne A van Galen, Carlos Caldas, Anne Vincent-Salomon, John W.M. Martens, Germán Fg Rodríguez-González, Anita Langerød, Christine Desmedt, Helen Davies, Aquila Fatima, Anieta M. Sieuwerts, Kim Berentsen, Jorunn J Eyford, Michelle van der Vlugt-Daane, Marc J. van de Vijver, Wendy Wj Prager-Van der Smissen, Alastair M Thompson, Stian Knappskog, Markus Ringnér, Carolien Ch van Deurzen, Paul N. Span, Marion E Meijer-Van Me Gelder, Roberto Salgado, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Radboud university [Nijmegen], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Dana-Farber Cancer Institute [Boston], Department of Medical Oncology, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], University of Cambridge [UK] (CAM), Department of Radiation Oncology 874, Radboud University Medical Center [Nijmegen], Department of Laboratory Medicine, University of Queensland [Brisbane], Department Medical Oncology, University of Antwerp (UA), Department of Pathology, Ospedale 'Mater Salutis', Beckman Research Institute [Duarte, CA], University of Iceland [Reykjavik], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, 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), Department of Tumor Biology, Institut Curie [Paris], MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), University of Bergen (UiB), Esso UK Ltd, Department of Exploration, Esso UK Ltd, Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Baobab, Département PEGASE [LBBE] (PEGASE), 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)-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)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), 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), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Oslo University Hospital Radiumhospitalet, Department of Molecular Biology [Nijmegen], Sagot, Marie-France, Radboud University [Nijmegen], Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical Oncology, Pathology, Fondation Synergie Lyon Cancer [Lyon], CCA -Cancer Center Amsterdam, Lakhani, Sunil R [0000-0003-1879-2555], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Biomedical, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome, Article, General Biochemistry, Genetics and Molecular Biology, CDH1, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Basic Science, SDG 3 - Good Health and Well-being, Breast Cancer, Genetics, medicine, PTEN, 1112 Oncology and Carcinogenesis, Molecular Biology, Cancer, 0604 Genetics, Multidisciplinary, Oncogene, biology, Human Genome, GATA3, Médecine pathologie humaine, General Chemistry, Sciences bio-médicales et agricoles, medicine.disease, Cell Cycle Gene, 3. Good health, Cancérologie, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Engineering sciences. Technology
Abstract: A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2016
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15. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Author: John W.M. Martens, Sandrine Boyault, David Jones, Stefania Tommasi, Jeong-Yeon Lee, Germán Fg Rodríguez-González, Inigo Martincorena, Sung-Min Ahn, Alastair M Thompson, Manasa Ramakrishna, Gilles Thomas, Helen Davies, Savitri Krishnamurthy, Stian Knappskog, Steven Van Laere, Lucy Stebbings, Andrea L. Richardson, Andrew Tutt, Anne Lise Børresen-Dale, Olafur Oa Stefansson, Sunil R. Lakhani, Michiel M. Smid, Gerrit Gk Hooijer, Young Seok Ju, Tari Ta King, Rebecca Shepherd, Luc Dirix, Xavier Pivot, Adam Butler, Aquila Fatima, Peter Pt Simpson, Serena Nik-Zainal, Sancha Martin, Hyung-Yong Kim, Hendrik G. Stunnenberg, Jos Jonkers, Michael R. Stratton, Jon W. Teague, Se Jin Jang, Sandro Morganella, Ville Mustonen, Moritz Gerstung, Gu Kong, Carlos Caldas, Anne Vincent-Salomon, Anieta M. Sieuwerts, Lucy R. Yates, Sarah O’Meara, Peter B. Vermeulen, Dominik Glodzik, Peter Van Loo, Naoto T. Ueno, Arie B. Brinkman, Stuart McLaren, Yang Li, Marc J. van de Vijver, Laura Van't Veer, P. Andrew Futreal, Markus Ringnér, Christos Sotiriou, Ewan Birney, Kamna Ramakrishnan, Miriam Ragle Aure, Johan Staaf, Jane E. Brock, Benita Kiat Tee Bk Tan, Alain Viari, Xueqing Zou, Anita Langerød, David C. Wedge, Hee Jin Lee, Christine Desmedt, Gilles Romieu, Paul N. Span, Jorunn E. Eyfjord, Annegien Broeks, Isabelle Treilleux, Åke Borg, Colin Ca Purdie, Ole Christian Lingjærde, Gert Van den Eynden, John A. Foekens, Serge Dronov, Andrew Menzies, Peter J. Campbell, Iris Pauporté, Ludmil B. Alexandrov, Keiran Raine, The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Radboud university [Nijmegen], Oslo University Hospital Radiumhospitalet, University of Oslo (UiO), Gachon University Hospital, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Brigham and Women's Hospital [Boston], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Algemeen Ziekenhuis St Augustinus Oncology, Dana-Farber Cancer Institute [Boston], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Ulsan, NASA Johnson Space Center (JSC), NASA, University of Stuttgart, Esso UK Ltd, Department of Exploration, Esso UK Ltd, Department of Computer Science & Engineering [Riverside] (CSE), University of California [Riverside] (UCR), University of California-University of California, Department of Geriatric Medicine [Singapore] (Alexandra Hospital), Institut national du cancer [Boulogne] (INCA), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Department of Pathology [Dundee], Ninewells Hospital and Medical School [Dundee], Canary Institute for Cancer Research (ICIC), Department of Biochemistry and Physiology, Faculty of Health Sciences, University of Las Palmas de Gran Canaria (ULPGC), 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), Department of Medical Oncology [Rotterdam], Cancer Genomics Centre, University of Queensland [Brisbane], University of Iceland [Reykjavik], Beckman Research Institute [Duarte, CA], 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Antwerp (UA), European Central Bank (ECB), European Central Bank, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Tumor Biology, Institut Curie [Paris], University of Cambridge [UK] (CAM), Division of Diagnostic Oncology, Netherlands Cancer Institute, Agendia BV, Breakthrough Breast Cancer Centre, London Institute of Cancer, University of Bergen (UiB), National Cancer Centre Singapore (NCCS), National Cancer Centre Singapore, Division of Molecular Biology, National Institutes of Natural Sciences, The Graduate University for Advanced Studies, Baobab, Département PEGASE [LBBE] (PEGASE), 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)-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)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), 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), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Department of Radiation Oncology 874, Radboud University Medical Center [Nijmegen], Department of Laboratory Medicine, Department Medical Oncology, Department of Pathology, Ospedale 'Mater Salutis', Goddard Earth Sciences and Technology and Research (GESTAR), NASA-Universities Space Research Association (USRA), Department of Molecular Biology [Nijmegen], Department of Organismic and Evolutionary Biology [Cambridge] (OEB), Harvard University [Cambridge], Department of Computing [London], Biomedical Image Analysis Group [London] (BioMedIA), Imperial College London-Imperial College London, Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Sagot, Marie-France, Radboud University [Nijmegen], University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nik-Zainal, Serena [0000-0001-5054-1727], Zou, Xueqing [0000-0003-1143-1028], Caldas, Carlos [0000-0003-3547-1489], Apollo - University of Cambridge Repository, Medical Oncology, Harvard University, Fondation Synergie Lyon Cancer [Lyon], CCA -Cancer Center Amsterdam, Pathology, Erasmus University Medical Center [Rotterdam], University of Oslo ( UiO ), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Netherlands Cancer Institute ( NKI ), Institut Jules Bordet, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ), NASA Johnson Space Center ( JSC ), Department of Computer Science & Engineering [Riverside] ( CSE ), University of California [Riverside] ( UCR ), Institut national du cancer [Boulogne] ( INCA ), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Department of Medical Oncology, Erasmus Medical Center Rotterdam, Josephine Nefkens Institute and Cancer Genomics Centre, University of Las Palmas de Gran Canaria ( ULPGC ), 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 ), Erasmus MC, Beckman Research Institute, Centre de Recherche en Cancérologie de Lyon ( 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 ), University of Antwerp ( UA ), European Central Bank ( ECB ), U 830, Institut National de la Santé et de la Recherche Médicale, Institut Curie, University of Cambridge [UK] ( CAM ), University of Bergen ( UIB ), National Cancer Centre Singapore ( NCCS ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), 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 ), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale ( ERABLE ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Goddard Earth Sciences and Technology and Research ( GESTAR ), NASA-Universities Space Research Association ( USRA ), Department of Organismic and Evolutionary Biology ( OEB ), and Biomedical Image Analysis Group [London] ( BioMedIA )
Subjects: 0301 basic medicine, DNA Replication, Male, Mutation rate, DNA repair, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Biology, medicine.disease_cause, Genome, Cohort Studies, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Mutation Rate, medicine, Humans, Gene, Molecular Biology, Genetics, Mutation, Multidisciplinary, [ SDV ] Life Sciences [q-bio], Genome, Human, Recombinational DNA Repair, DNA, Neoplasm, Genomics, Oncogenes, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Mutagenesis, Human genome, Female, Engineering sciences. Technology
Abstract: Item does not contain fulltext We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
Published: 2016
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16. Blocking SHH/Patched Interaction Triggers Tumor Growth Inhibition through Patched-Induced Apoptosis.

Author: Bissey PA, Mathot P, Guix C, Jasmin M, Goddard I, Costechareyre C, Gadot N, Delcros JG, Mali SM, Fasan R, Arrigo AP, Dante R, Ichim G, Mehlen P, and Fombonne J
Subjects: Animals, Cell Line, Tumor, Cell Proliferation physiology, Chick Embryo, Heterografts, Humans, Mice, Signal Transduction physiology, Zebrafish, Apoptosis physiology, Hedgehog Proteins metabolism, Neoplasms metabolism, Neoplasms pathology, Patched Receptors metabolism
Abstract: The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signaling, causally linked to tumor progression, have become rational targets for cancer therapy. However, Smoothened (SMO) inhibitors have failed to show clinical benefit in patients with cancers displaying SHH autocrine/paracrine expression. We reported earlier that the SHH receptor Patched (PTCH) is a dependence receptor that triggers apoptosis in the absence of SHH through a pathway that differs from the canonical one, thus generating a state of dependence on SHH for survival. Here, we propose a dual function for SHH: its binding to PTCH not only activates the SHH canonical pathway but also blocks PTCH-induced apoptosis. Eighty percent, 64%, and 8% of human colon, pancreatic, and lung cancer cells, respectively, overexpressed SHH at transcriptional and protein levels. In addition, SHH-overexpressing cells expressed all the effectors of the PTCH-induced apoptotic pathway. Although the canonical pathway remained unchanged, autocrine SHH interference in colon, pancreatic, and lung cell lines triggered cell death through PTCH proapoptotic signaling. In vivo , SHH interference in colon cancer cell lines decreased primary tumor growth and metastasis. Therefore, the antitumor effect associated to SHH deprivation, usually thought to be a consequence of the inactivation of the canonical SHH pathway, is, at least in part, because of the engagement of PTCH proapoptotic activity. Together, these data strongly suggest that therapeutic strategies based on the disruption of SHH/PTCH interaction in SHH-overexpressing cancers should be explored. SIGNIFICANCE: Sonic Hedgehog-overexpressing tumors express PTCH-induced cell death effectors, suggesting that this death signaling could be activated as an antitumor strategy., (©2020 American Association for Cancer Research.)
Published: 2020
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17. Prediction of Breast Cancer Treatment-Induced Fatigue by Machine Learning Using Genome-Wide Association Data.

Author: Lee S, Deasy JO, Oh JH, Di Meglio A, Dumas A, Menvielle G, Charles C, Boyault S, Rousseau M, Besse C, Thomas E, Boland A, Cottu P, Tredan O, Levy C, Martin AL, Everhard S, Ganz PA, Partridge AH, Michiels S, Deleuze JF, Andre F, and Vaz-Luis I
Abstract: Background: We aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data., Methods: We accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic ( P < .001) variables, a multivariable preconditioned random-forest regression model was built and validated on a hold-out subset to predict fatigue. Gene set enrichment analysis identified key biological correlates (MetaCore). All statistical tests were 2-sided., Results: Statistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association ( P < .001) with the different fatigue endpoints, although there were no genome-wide statistically significant ( P < 5.00 × 10 -8 ) associations. Only for Cognitive Fatigue, the predictive ability of the genomic multivariable model was statistically significantly better than random (area under the curve = 0.59, P = .01) and marginally improved with clinical variables (area under the curve = 0.60, P = .005). Single nucleotide polymorphisms found to be associated ( P < .001) with Cognitive Fatigue belonged to genes linked to inflammation (false discovery rate adjusted P = .03), cognitive disorders ( P = 1.51 × 10 -12 ), and synaptic transmission ( P = 6.28 × 10 -8 )., Conclusions: Genomic analyses in this large cohort of breast cancer survivors suggest a possible genetic role for severe Cognitive Fatigue that warrants further exploration., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Published: 2020
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18. Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer.

Author: Adam J, Le Stang N, Rouquette I, Cazes A, Badoual C, Pinot-Roussel H, Tixier L, Danel C, Damiola F, Damotte D, Penault-Llorca F, and Lantuéjoul S
Subjects: Antibodies, Monoclonal immunology, B7-H1 Antigen genetics, Humans, B7-H1 Antigen immunology, B7-H1 Antigen standards, Carcinoma, Non-Small-Cell Lung genetics, Genetic Testing standards, Immunohistochemistry methods, Lung Neoplasms genetics
Abstract: Background: Various programed death ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed and used in clinical trials in association with different drugs. In order to harmonize and make PD-L1 testing in non-small-cell lung cancer (NSCLC) widely available, we conducted a multicenter study comparing PD-L1 standardized assays and laboratory-developed tests (LDTs)., Methods: IHC with five anti-PD-L1 monoclonal antibodies (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers using Dako Autostainer Link 48 (3 centers), Leica Bond (2 centers) or Ventana BenchMark Ultra (2 centers) platforms. For each matching platform, 22C3, 28-8 and SP263 assays were performed. For nonmatching platforms and other antibodies, LDTs were developed in each center. A total of 35 stainings were performed for each case across different platforms and antibodies. PD-L1 staining was assessed in tumor cells and immune cells by seven trained thoracic pathologists. For statistical analysis, 1%, 50% and 1%, 5%, 10% expression thresholds were used for tumor cells and immune cells, respectively., Results: 28-8, 22C3 and SP263 assays were highly concordant for tumor cells staining across the five Dako or Ventana platforms. Among 27 LDTs developed in 7 centers on Dako, Ventana and Leica platforms, 14 (51.8%) demonstrated similar concordance when compared with reference assays for tumor cell staining. Clone SP263 achieved the highest concordance rate across all platforms. Lower concordance was observed for immune cells staining when using a four categories scale., Conclusion: 28-8, 22C3 and SP263 assays had close analytical performance for tumor cell staining across seven centers. Some LDTs on Dako, Ventana and Leica platforms achieved similar concordance, but caution is warranted for their validation. These LDTs will be further validated in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.
Published: 2018
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19. Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS G12D -driven Pancreatic Tumorigenesis.

Author: Chuvin N, Vincent DF, Pommier RM, Alcaraz LB, Gout J, Caligaris C, Yacoub K, Cardot V, Roger E, Kaniewski B, Martel S, Cintas C, Goddard-Léon S, Colombe A, Valantin J, Gadot N, Servoz E, Morton J, Goddard I, Couvelard A, Rebours V, Guillermet J, Sansom OJ, Treilleux I, Valcourt U, Sentis S, Dubus P, and Bartholin L
Abstract: Background & Aims: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive., Methods: We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRI CA ) in the pancreatic acinar compartment., Results: We observed that TβRI CA expression induced acinar-to-ductal metaplasia (ADM) reprogramming, eventually facilitating the onset of KRAS G12D -induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1β , Sox9, and Hes1 ., Conclusions: We demonstrate that TGFβ pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRAS G12D -dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients.
Published: 2017
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19 results on '"Fondation Synergie Lyon Cancer [Lyon]"'

1. Genetic analysis of lung cancer and the germline impact on somatic mutation burden

2. Gene signature of circulating platelet-bound neutrophils is associated with poor prognosis in cancer patients

3. Comprehensive Genome Profiling in Patients With Metastatic Non-Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

4. Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming

5. The circular RNome of primary breast cancer

6. Apport et défis des Big Data en cancérologie

7. Prediction of Breast Cancer Treatment-Induced Fatigue by Machine Learning Using Genome-Wide Association Data

8. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

9. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer

10. Comprehensive molecular classification of localized prostate adenocarcinoma reveals a tumour subtype predictive of non-aggressive disease

11. A stemness-related ZEB1–MSRB3 axis governs cellular pliancy and breast cancer genome stability

12. BCL2 mutations do not confer adverse prognosis in follicular lymphoma patients treated with rituximab

13. GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

14. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

15. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

16. Blocking SHH/Patched Interaction Triggers Tumor Growth Inhibition through Patched-Induced Apoptosis.

17. Prediction of Breast Cancer Treatment-Induced Fatigue by Machine Learning Using Genome-Wide Association Data.

18. Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer.

19. Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS G12D -driven Pancreatic Tumorigenesis.

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19 results on '"Fondation Synergie Lyon Cancer [Lyon]"'

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