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1. A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression

Author

André Nicolas, Céline Desbrousses, Mariona Suñol, Sylvain Baulande, Fabiana Lubieniecki, Sandrine Arrufat, David Gentien, Nanor Sirab, Eric Letouzé, Clément Hua, Simon Saule, Elodie Chapeaublanc, Paul Fréneaux, Fariba Nemati, Laurie Tonon, Claude Houdayer, Odette Mariani, Alain Viari, Magalie Larcher, Xavier Sastre-Garau, Sacha Reichman, Daniela Ottaviani, Nathalie Cassoux, Marion Gauthier-Villars, Isabelle Aerts, Céline Vallot, Guillermo Chantada, Aurélien de Reyniès, Genoveva Correa Llano, Liliana Mirabal-Ortega, Livia Lumbroso-Le Rouic, Angel M. Carcaboso, Jérôme Couturier, Dominique Stoppa-Lyonnet, Hervé Brisse, Jaume Català-Mora, Florent Dufour, Isabelle Bernard-Pierrot, François Doz, Meriem Sefta, Paula Schaiquevich, Emmanuel Barillot, Laurence Desjardins, Rosario Aschero, Nabila Elarouci, Celio Pouponnot, Tatiana Popova, F. Radvanyi, Catherine Dehainault, Jing Liu, Gabriela Lamas, Narjesse Karboul, Didier Decaudin, Alexandre Matet, Lisa Golmard, Céline Brulard, Sylvain Guibert, Guillem Pascual-Pasto, Olivier Goureau, Anne Biton, Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University, 75005, Paris, France, Sorbonne Université (SU), Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, 75013, Paris, France, 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), Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas, 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]-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), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Hospital Nacional de Pediatría J.P. Garrahan, Centre Léon Bérard [Lyon], Département de Biologie des Tumeurs, Institut Curie [Paris], Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Recherche Translationnelle, Centre de recherche de l'Institut Curie [Paris], Genomics Consulting (GeCo), Institut de Recerca Pediàtrica Hospital Sant Joan de Déu [Barcelona, Spain], Hospital Sant Joan de Déu [Barcelona], Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), CHU Rouen, Normandie Université (NU), Département d'Imagerie Médicale [Institut Curie], Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), CHI Créteil, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), and Pouponnot, Celio

Subjects
Male, Retinal Ganglion Cells, genetic structures, Cell, Gene Expression, General Physics and Astronomy, Stem cell marker, Metastasis, Transcriptome, 0302 clinical medicine, Neoplasm Metastasis, Cancer genetics, N-Myc Proto-Oncogene Protein, 0303 health sciences, Multidisciplinary, Retinoblastoma, 3. Good health, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Retinal Cone Photoreceptor Cells, Female, Science, Retinal Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Malignancy, Article, General Biochemistry, Genetics and Molecular Biology, Eye cancer, Paediatric cancer, Genetic Heterogeneity, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, medicine, Humans, Transcriptomics, Data mining, 030304 developmental biology, Retina, Infant, Cancer, General Chemistry, Cell Dedifferentiation, DNA Methylation, medicine.disease, eye diseases, Mutation, Cancer research, sense organs
Abstract

Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas., Retinoblastoma is the most frequent intraocular paediatric malignancy whose molecular basis remains poorly understood. Here, the authors perform multi-omic analysis and identify two subtypes; one in a cone differentiated state and one more aggressive showing cone dedifferentiation and expressing neuronal markers.

Published
2021
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2. 691 Identification of shared tumor epitopes from endogenous retroviruses inducing high avidity cytotoxic T cells for cancer immunotherapy

Author

Rasha Boulos, Stéphane Depil, Paola Bonaventura, Virginie Mutez, Yann Estornes, Christophe Caux, Jenny Valladeau-Guilemond, Alain Viari, Laurie Tonon, Vincent Alcazer, Juliette Martin, and Nicolas Chuvin

Subjects
Pharmacology, Cancer Research, High avidity, medicine.medical_treatment, Immunology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Endogenous retrovirus, Biology, Epitope, Oncology, Cancer immunotherapy, medicine, Cancer research, Molecular Medicine, Immunology and Allergy, Cytotoxic T cell, Identification (biology), RC254-282
Abstract

BackgroundHuman endogenous retroviruses (HERVs) are aberrantly expressed by tumor cells and may represent a source of T cell epitopesMethodsUsing TCGA pancancer RNAseq data (n=8,893 samples), we developed a bioinformatics-based method to select cancer-specific HERVs associated with a cytotoxic T cell response (“cyt-HERVs”) and identify shared T cell epitope candidates. T cells were primed with selected short and long peptide candidates from HLA-A2+ healthy donors. Peptide-specific dextramers were used to sort and expand specific CD8+ T cell clones and determine their TCR sequences and avidity. Cytotoxicity was assessed against HERV-expressing tumor cell lines and patient-derived organoids using Incucyte and Nanolive technologies (Flowchart, figure 1).ResultsIn a pancancer analysis, we identified 57 HML-2/HERV-K HLA-A*0201 epitope candidates from 27 distinct open reading frames. Six shared HLA-A2 strong binders 9-mer peptides, present on multiple HERVs located on different chromosomes, and with translational evidence found in mass spectrometry public datasets, were selected and synthetized. In vitro HLA binding assay confirmed peptide-HLA affinity. Priming assays showed the presence of specific CD8+ T cells leading to polyfunctional IFN-γ+ TNF-α+ T cell responses with upregulation of the degranulation marker CD107A upon co-culture with peptide-pulsed T2 cells. Synthetic long peptides containing the epitopes were used to confirm the correct processing by antigen-presenting cells. The functionality of the sorted T cell clones was confirmed using an Elispot assay (GrzB+ IFN-γ+). Their sequenced TCRs were predicted to stably interact with their respective MHC-peptide complexes in a 3D model. This was confirmed by measurement of the functional avidity, which was in the same order as CMV-specific T cell clones. HERV-specific CD8+ T cells induced specific cell death of HLA-A2+ cancer cell lines, associated with IFN-g production, in a HLA-A2 restricted manner. Finally, pre-existing HERV-specific CD8+ T cells were identified using dextramers among tumor infiltrating lymphocytes (TILs) from cancer patients. HERV-specific T cells co-cultured with patient derived organoids showed signs of activation with lysis of the organoid.ConclusionsOur bioinformatics-based approach allowed us to identify shared HERV-derived CD8+ T cell epitopes specifically expressed by tumor cells and inducing high avidity T cell clones able to kill tumor cells in a class I-restricted manner. The detection of TILs recognizing HERV peptides suggests natural presentation of these epitopes in the tumors. These HERV-derived epitopes may thus represent relevant targets for the development of new cancer vaccines or T cell-based therapies, especially in tumors with low mutational burden.Abstract 691 Figure 1Graphical flowchart of HERV antigen validation. Graphical representation of the flowchart used to identify and validate specific CD8+ T cells for shared tumor epitopes from endogenous retroviruses http://dx.doi.org/10.1136/jitc-2021-SITC2021.691

Published
2021
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3. 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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4. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

Author

Marta Gut, Iris Pauporté, Cécile Mannina, Sancha Martin, Michael R. Stratton, Frédérique Penault-Llorca, Vincent Le Texier, Laurent Arnould, Pierre Saintigny, Marie-Christine Mathieu, P. Fumoleau, Xavier Pivot, Jean-François Deleuze, Hélène Blanché, Anthony Ferrari, Janice Kielbassa, Eskeatnaf Mulugeta, Olivier Tredan, Sandrine Boyault, Anne Vincent-Salomon, Thomas Bachelot, Emilie Thomas, Jean-Yves Pierga, Odette Mariani, Suzette Delaloge, Ivo Gut, Hervé Bonnefoi, Fabien Calvo, Frédéric Bibeau, Alain Viari, Serena Nik-Zainal, Anne-Sophie Sertier, Gilles Romieu, Maria Rios, Gaëtan MacGrogan, Jocelyne Jacquemier, Laurie Tonon, Gilles Thomas, Jean-Marc Ferrero, Isabelle Treilleux, Daniel Birnbaum, Catherine Bouteille, Carole Tarpin, Centre Léon Bérard [Lyon], Génétique et Biologie du Développement, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), 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), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Gustave Roussy (IGR), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Ressources Biologiques [Paris], Institut Curie [Paris], Département de pathologie, Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Department of Medical Oncology [Lyon], UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, UNICANCER, Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Pôle de Chirurgie Oncologique générale, Gynécologique et Mammaire [Centre Antoine-Lacassagne], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-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), Chirurgie gynécologique, mammaire et réparatrice [Saint-Etienne], Clinique Mutualiste Chirurgicale [Saint-Étienne], Direction de la recherche [Gustave Roussy], Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), The Wellcome Trust Sanger Institute [Cambridge], Institut National du Cancer [Boulogne Billancourt] (INC), 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), 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), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Université de Franche-Comté ( UFC ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Institut Gustave Roussy ( IGR ), Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), Institut Curie, Institut Bergonié - CRLCC Bordeaux, Physico-Chimie-Curie ( PCC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut de Cancérologie de Lorraine - Alexis Vautrin ( ICL ), CRLCC Antoine Lacassagne, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université ( AMU ), Centre for Genomic Regulation [Barcelona] ( CRG ), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] ( CNAG ), Institut National du Cancer [Boulogne Billancourt] ( INC ), 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 ), 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 ), Nik-Zainal Abidin, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Sagot, Marie-France, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Institut Paoli Calmettes, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Université Claude Bernard Lyon 1 ( UCBL ), and 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 )

Subjects
0301 basic medicine, DNA Copy Number Variations, Receptor, ErbB-2, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Breast Neoplasms, Biology, Genome, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Gene duplication, medicine, Humans, Copy-number variation, skin and connective tissue diseases, Genetics, Multidisciplinary, Whole Genome Sequencing, [ SDV ] Life Sciences [q-bio], Gene Expression Profiling, Estrogen Receptor alpha, Gene Amplification, General Chemistry, Amplicon, medicine.disease, 3. Good health, Gene expression profiling, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Human genome, Female, Receptors, Progesterone, Transcriptome
Abstract

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal–basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage–fusion–bridge mechanism., Breast cancer is separated into multiple subtypes based on the expression of HER2 and hormone receptors. Here, the authors report the whole genome sequence of 64 HER2 positive tumours and show that these can be further separated into four groups with different gene expression profiles and genomic features.

Published
2016
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5. EZH2 alterations in follicular lymphoma: biological and clinical correlations

Author

Julien Lazarovici, Gilles Salles, Marjorie Carrère, Lenaïg Mescam-Mancini, Alain Viari, Emilie Sohier, Olivier Casasnovas, Corinne Haioun, Sandrine Boyault, Sebastien Taix, Luc Xerri, Laurie Tonon, Bettina Fabiani, Sylvain Mareschal, Sandrine Hayette, Bruno Tesson, Sarah Huet, Fabrice Jardin, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Carnot Lymphome (CALYM), Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas, 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]-Université Claude Bernard Lyon 1 (UCBL), Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Institut Carnot CALYM [Pierre-Benite], and Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)

Subjects
Adult, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Follicular lymphoma, macromolecular substances, Biology, Methylation, Polymorphism, Single Nucleotide, Disease-Free Survival, 03 medical and health sciences, Histone H3, symbols.namesake, Cell Line, Tumor, medicine, Humans, Enhancer of Zeste Homolog 2 Protein, Lymphoma, Follicular, Aged, Sanger sequencing, Regulation of gene expression, Sequence Analysis, RNA, EZH2, Histone-Lysine N-Methyltransferase, Hematology, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, Histone methyltransferase, Mutation, Histone Methyltransferases, Mutation testing, symbols, Cancer research, Original Article, Female
Abstract

The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36–0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.

Published
2017
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6. A Comprehensive Assessment of Somatic Mutation Calling in Cancer Genomes

Author

Marc Dabad, John Douglas Mcpherson, Xose S. Puente, Liu Xi, Ivo Gut, Anne-Marie Patch, Semin Lee, Cyriac Kandoth, Ruben M. Drews, Charlotte Anderson, Eivind Hovig, Paul C. Boutros, Peter J. Campbell, Louis Letourneau, Paolo Ribeca, Hidewaki Nakagawa, Natalie Jäger, Daniel Vodak, Thomas J. Hudson, Anne Sophie Sertier, Pablo H. Hennings-Yeomans, John Zhang, Philip Ginsbach, Laurie Tonon, Emanuele Raineri, Sahil Seth, Sophia Derdak, Benedikt Brors, David T. W. Jones, Minghui He, Sergi Beltran, Rafael Valdés-Mas, David Torrents, Singer Ma, Myron Peto, Nagarajan Paramasivam, Matthew D. Eldridge, Robert E. Denroche, Paul T. Spellman, Francesc Castro Giner, Roland Eils, Timothy Beck, Sigve Nakken, Daniela S. Gerhard, Lawrence E. Heisler, Jared T. Simpson, Víctor Quesada, Rolf Kabbe, Andy G. Lynch, Patrick S. Tarpey, Lawrence Bower, Akihiro Fujimoto, Barbara Hutter, Matthias Schlesner, Marta Gut, Ivo Buchhalter, David A. Wheeler, Takafumi N. Yamaguchi, Simon Heath, Nicholas J. Harding, and Tyler Alioto

Subjects
Genetics, Whole genome sequencing, 0303 health sciences, Concordance, Cancer, Genomics, Computational biology, Biology, medicine.disease, Genome, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), medicine, 030304 developmental biology
Abstract

The emergence of next generation DNA sequencing technology is enabling high-resolution cancer genome analysis. Large-scale projects like the International Cancer Genome Consortium (ICGC) are systematically scanning cancer genomes to identify recurrent somatic mutations. Second generation DNA sequencing, however, is still an evolving technology and procedures, both experimental and analytical, are constantly changing. Thus the research community is still defining a set of best practices for cancer genome data analysis, with no single protocol emerging to fulfil this role. Here we describe an extensive benchmark exercise to identify and resolve issues of somatic mutation calling. Whole genome sequence datasets comprising tumor-normal pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, were shared within the ICGC and submissions of somatic mutation calls were compared to verified mutations and to each other. Varying strategies to call mutations, incomplete awareness of sources of artefacts, and even lack of agreement on what constitutes an artefact or real mutation manifested in widely varying mutation call rates and somewhat low concordance among submissions. We conclude that somatic mutation calling remains an unsolved problem. However, we have identified many issues that are easy to remedy that are presented here. Our study highlights critical issues that need to be addressed before this valuable technology can be routinely used to inform clinical decision-making.

Published
2014
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7. A comprehensive multicenter comparison of whole genome sequencing pipelines using a uniform tumor-normal sample pair

Author

Benedikt Brors, Hidewaki Nakagawa, Peter J. Campbell, Susanne Gröbner, Natalie Jäger, Jones Dtw, Fujimoto A, Sasithorn Chotewutmontri, Patrick S. Tarpey, Keiran Raine, Matthias Schlesner, Liu Xi, Sophia Derdak, Stefan M. Pfister, Paolo Ribeca, David A. Wheeler, Takafumi N. Yamaguchi, John Douglas Mcpherson, Adam Butler, Jonathon Hinton, Sertier A, Christopher Previti, Peter Lichter, Michael Heinold, Andrey Korshunov, Jon W. Teague, Lawrence E. Heisler, Rolf Kabbe, Robert E. Denroche, Lucy Stebbings, Timothy Beck, Barbara Hutter, Ivo Buchhalter, Andy Menzies, Gut M, Roland Eils, Gut I, Paul C. Boutros, Nicolle Diessl, Lars Feuerbach, Rebecca Shepherd, Sabine Schmidt, Tyler Alioto, Laurie Tonon, Nicholas J. Harding, and David T. Jones

Subjects
Whole genome sequencing, Genetics, 0303 health sciences, Library preparation, Sample (statistics), Genomics, Benchmarking, Computational biology, Biology, Deep sequencing, 03 medical and health sciences, 0302 clinical medicine, Coverage ratio, 030220 oncology & carcinogenesis, Clinical care, 030304 developmental biology
Abstract

As next-generation sequencing becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Through the International Cancer Genome Consortium (ICGC), we compared sequencing pipelines at five independent centers (CNAG, DKFZ, OICR, RIKEN and WTSI) using a single tumor-blood DNA pair. Analyses by each center and with one standardized algorithm revealed significant discrepancies. Although most pipelines performed well for coding mutations, library preparation methods and sequencing coverage metrics clearly influenced downstream results. PCR-free methods showed reduced GC-bias and more even coverage. Increasing sequencing depth to ~100x (two- to three-fold higher than current standards) showed a benefit, as long as the tumor:control coverage ratio remained balanced. To become part of routine clinical care, high-throughput sequencing must be globally compatible and comparable. This benchmarking exercise has highlighted several fundamental parameters to consider in this regard, which will allow for better optimization and planning of both basic and translational studies.

Published
2014
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8. Abstract P6-07-13: New insights on HER2 amplification from the constitutional and somatic standpoints: Results from the ICGC and SIGNAL/Phare studies

Author

Pierre Saintigny, Gaëtan MacGrogan, D Birbaum, Xavier Pivot, V Letexier, G Romieux, Laurent Arnould, Alain Viari, Anne Vincent-Salomon, Iris Pauporté, S Boyault, A Ferrari, A-S Sertier, David Cox, Isabelle Treilleux, Janice Kielbassa, Emilie Thomas, and Laurie Tonon

Subjects
Genetics, Whole genome sequencing, Cancer Research, Genetic heterogeneity, Cancer, Genome-wide association study, Amplicon, Biology, medicine.disease_cause, medicine.disease, Genome, Breast cancer, Oncology, medicine, skin and connective tissue diseases, Carcinogenesis
Abstract

Background: HER2-positive (HER2+) breast cancers are defined by the amplification and/or overexpression of the human epidermal growth factor receptor (HER2/ERBB2) gene on chromosome region 17q12. Although anti-HER2 targeted therapies have greatly improved treatment of HER2+ breast cancer, the magnitude of benefit varies widely between patients. Deciphering the genomic and genetic heterogeneity of HER2+ breast cancer may provide a basis to better understand their natural history, opening new avenues of treatment. Methods: As part of the ICGC Breast Cancer Working Group effort, we combined whole genome sequencing and transcriptomic analyses of 64 HER2+ primary invasive carcinomas, and a genome wide association study (GWAS) of over 9.836 breast cancer patients in the prospective SIGNAL/PHARE cohort (NCT00381901 – RECF1098). Results: Using WGS data we precisely delineate the ERBB2 amplicon as a 106 kb region involving six genes and show that the amplification mechanism was consistent with breakage-fusion-bridge (BFB) cycles. Four RNA expression-based groups were identified, displaying specific genomic alterations in terms of amplification, rearrangements and mutations. On other hand, GWAS analyses failed to identify any constitutional variants associated with HER2 amplification. Discussion: By combining whole genome sequencing and expression analysis, we provide evidence showing that HER2+ tumours display considerably more molecular heterogeneity than previously reported. These results are reinforced with the lack of association between any genetic variants and HER2 amplification from GWAS analyses. Taken as a whole, these results suggest that HER2+ breast cancers do not represent per se a homogeneous subtype, but are distributed along the whole breast cancer spectrum, from ER-positive luminal to ER-negative basal phenotype. Genome alterations present in HER2+ tumors are in accordance with these phenotypes, and it is likely that the HER2 amplification is a secondary event in the course of tumorigenesis, not favored by any particular constitutional or somatic genetic variants. Citation Format: Vincent-Salomon A, Ferrari A, Pivot X, Macgrogan G, Arnould L, Treilleux I, Romieux G, Sertier A-S, Thomas E, Tonon L, Boyault S, Kielbassa J, Letexier V, Pauporte I, Birbaum D, Saintigny P, Cox D, Viari A. New insights on HER2 amplification from the constitutional and somatic standpoints: Results from the ICGC and SIGNAL/Phare studies. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-13.

Published
2016
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9. TFM-Explorer: mining cis-regulatory regions in genomes

Author

Hélène Touzet, Jean-Stéphane Varré, Laurie Tonon, Bioinformatics and Sequence Analysis (BONSAI), Laboratoire d'Informatique Fondamentale de Lille (LIFL), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria), and Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)

Subjects
Web server, Genomics, Computational biology, Biology, computer.software_genre, Genome, Mice, Genetics, Transcriptional regulation, Animals, Data Mining, Humans, Regulatory Elements, Transcriptional, Binding site, Transcription factor, Gene, Skin, Internet, Binding Sites, Muscles, Brain, Articles, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Rats, Regulatory sequence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, Software, Transcription Factors
Abstract

International audience; DNA-binding transcription factors (TFs) play a central role in transcription regulation, and computational approaches that help in elucidating complex mechanisms governing this basic biological process are of great use. In this perspective, we present the TFM-Explorer web server that is a toolbox to identify putative TF binding sites within a set of upstream regulatory sequences of genes sharing some regulatory mechanisms. TFM-Explorer finds local regions showing overrepresentation of binding sites. Accepted organisms are human, mouse, rat, chicken and drosophila. The server employs a number of features to help users to analyze their data: visualization of selected binding sites on genomic sequences, and selection of cis-regulatory modules. TFM-Explorer is available at http://bioinfo.lifl.fr/TFM.

Published
2010
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10. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing

Author

Matthew D. Eldridge, Sasithorn Chotewutmontri, Susanne Gröbner, Eivind Hovig, Ivo Gut, Minghui He, Hidewaki Nakagawa, Charlotte Anderson, Rafael Valdés-Mas, Lars Feuerbach, Sergi Beltran, Adam Butler, Nagarajan Paramasivam, John Douglas Mcpherson, Akihiro Fujimoto, Ann-Marie Patch, Ivo Buchhalter, Laurie Tonon, Stefan M. Pfister, Víctor Quesada, Jon W. Teague, Sabine Schmidt, David T. W. Jones, Sahil Seth, David Torrents, Singer Ma, Marta Gut, Semin Lee, Robert E. Denroche, Carlos López-Otín, Andy G. Lynch, David A. Wheeler, Takafumi N. Yamaguchi, Lucy Stebbings, Ruben M. Drews, Roland Eils, Marc Dabad, Tyler Alioto, Barbara Hutter, Rebecca Shepherd, Peter Lichter, Sigve Nakken, Daniel Vodak, Simon Heath, Rolf Kabbe, Christopher Previti, Paul T. Spellman, Nicola Waddell, Jared T. Simpson, John V. Pearson, Timothy Beck, Patrick S. Tarpey, Daniela S. Gerhard, Andrew Menzies, Francesc Castro Giner, Paolo Ribeca, Nicholas J. Harding, Liu Xi, Nicolle Diessl, Emanuele Raineri, Lawrence E. Heisler, Jonathan Hinton, Xose S. Puente, Cyriac Kandoth, Natalie Jäger, David T. Jones, Matthias Schlesner, Louis Letourneau, Sean M. Grimmond, Elias Campo, Peter J. Campbell, Keiran Raine, Lawrence Bower, Michael Heinold, Andrey Korshunov, Thomas J. Hudson, Anne Sophie Sertier, Benedikt Brors, Sophia Derdak, Paul C. Boutros, Myron Peto, John Zhang, Philip Ginsbach, Alioto, Tyler S [0000-0002-2960-5420], Buchhalter, Ivo [0000-0003-0764-5832], Hutter, Barbara [0000-0002-9034-0329], Hovig, Eivind [0000-0002-9103-1077], Patch, Ann-Marie [0000-0001-6121-4019], Drews, Ruben [0000-0001-7360-4970], Raine, Keiran [0000-0002-5634-1539], Ribeca, Paolo [0000-0001-5599-3933], Giner, Francesc Castro [0000-0001-6111-0754], Heath, Simon C [0000-0002-9550-0897], Denroche, Robert E [0000-0003-2197-7083], Yamaguchi, Takafumi N [0000-0003-1082-3871], Seth, Sahil [0000-0003-4579-3959], Boutros, Paul C [0000-0003-0553-7520], Hudson, Thomas J [0000-0002-1376-4849], Gut, Ivo G [0000-0001-7219-632X], Apollo - University of Cambridge Repository, Universitat de Barcelona, University of St Andrews. School of Medicine, and University of St Andrews. Statistics

Subjects
Cancer genome sequencing, General Physics and Astronomy, Genome informatics, Lymphoid, Genètica mèdica, Human genetics, 2.1 Biological and endogenous factors, DNA sequencing, Aetiology, Càncer, Cancer genetics, Exome, Cancer, Genetics, Multidisciplinary, Genome, Leukemia, Genètica humana, Medical genetics, High-Throughput Nucleotide Sequencing, 3. Good health, Mutation (genetic algorithm), Personal genomics, Human, Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC], Ciències de la salut::Medicina [Àrees temàtiques de la UPC], Bioinformatics, Context (language use), QH426 Genetics, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Deep sequencing, RC0254, SDG 3 - Good Health and Well-being, Bioinformàtica, Humans, ddc:610, QH426, Whole genome sequencing, RC0254 Neoplasms. Tumors. Oncology (including Cancer), Genome, Human, Prevention, Human Genome, Mutació (Biologia), DAS, General Chemistry, Mutation (Biology), Leukemia, Lymphoid, Mutation, Medulloblastoma
Abstract

Financial support was provided by the consortium projects READNA under grant agreement FP7 Health-F4- 2008-201418, ESGI under grant agreement 262055, GEUVADIS under grant agreement 261123 of the European Commission Framework Programme 7, ICGC-CLL through the Spanish Ministry of Science and Innovation (MICINN), the Instituto de Salud Carlos III(ISCIII) and the Generalitat de Catalunya, Alioto, T.S., Buchhalter, I., Derdak, S., Hutter, B., Eldridge, M.D., Hovig, E., Heisler, L.E., Beck, T.A., Simpson, J.T., Tonon, L., Sertier, A.-S., Patch, A.-M., Jäger, N., Ginsbach, P., Drews, R., Paramasivam, N., Kabbe, R., Chotewutmontri, S., Diessl, N., Previti, C., Schmidt, S., Brors, B., Feuerbach, L., Heinold, M., Gröbner, S., Korshunov, A., Tarpey, P.S., Butler, A.P., Hinton, J., Jones, D., Menzies, A., Raine, K., Shepherd, R., Stebbings, L., Teague, J.W., Ribeca, P., Giner, F.C., Beltran, S., Raineri, E., Dabad, M., Heath, S.C., Gut, M., Denroche, R.E., Harding, N.J., Yamaguchi, T.N., Fujimoto, A., Nakagawa, H., Quesada, V., Valdés-Mas, R., Nakken, S., Vodák, D., Bower, L., Lynch, A.G., Anderson, C.L., Waddell, N., Pearson, J.V., Grimmond, S.M., Peto, M., Spellman, P., He, M., Kandoth, C., Lee, S., Zhang, J., Létourneau, L., Ma, S., Seth, S., Torrents, D., Xi, L., Wheeler, D.A., López-Otín, C., Campo, E., Campbell, P.J., Boutros, P.C., Puente, X.S., Gerhard, D.S., Pfister, S.M., McPherson, J.D., Hudson, T.J., Schlesner, M., Lichter, P., Eils, R., Jones, D.T.W., Gut, I.G.

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