title: A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.
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.
authors.affiliation: Synergie Lyon Cancer, Plateforme de bioinformatique 'Gilles Thomas' Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ferrari
authors.affiliation: Institut Curie, PSL Research University, Département de Pathologie, INSERM U934, 26 rue d'Ulm, 75248 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Centre Hospitalier Universitaire de Minjoz, UMR INSERM 1098, Boulevard A. Fleming, Besançon 25000, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pivot
authors.affiliation: Synergie Lyon Cancer, Plateforme de bioinformatique 'Gilles Thomas' Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Sertier
authors.affiliation: Synergie Lyon Cancer, Plateforme de bioinformatique 'Gilles Thomas' Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Thomas
authors.affiliation: Synergie Lyon Cancer, Plateforme de bioinformatique 'Gilles Thomas' Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Tonon
authors.affiliation: Plateforme de génomique des cancers, Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Boyault
authors.affiliation: Institut Curie, UMR 3215 CNRS, Génétique et biologie du développement, Epigénèse et développement des mammifères, U934 Inserm, 26 rue d'Ulm, 75248 Paris, France.
authors.forename: Eskeatnaf
authors.initials: E
authors.lastname: Mulugeta
authors.affiliation: Centre Léon Bérard, Département de Pathologie, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.affiliation: Département de Biopathologie, Unité Inserm U916, Institut Bergonié, 229 cours de l'Argonne, 33076 Bordeaux, France.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: MacGrogan
authors.affiliation: Centre Georges-François Leclerc et CRB Ferdinand Cabanne, 1 rue du Professeur Marion, Inserm U866-UBFC, 21000 Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.affiliation: Synergie Lyon Cancer, Plateforme de bioinformatique 'Gilles Thomas' Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Janice
authors.initials: J
authors.lastname: Kielbassa
authors.affiliation: Synergie Lyon Cancer, Plateforme de bioinformatique 'Gilles Thomas' Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Le Texier
authors.affiliation: Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blanché
authors.affiliation: Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Institut Paoli-Calmettes, Département de Pathologie, 232 Boulevard de Sainte-Marguerite, 13009 Marseille, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Jacquemier
authors.affiliation: Institut Gustave Roussy, Comité de Pathologie Mammaire, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Mathieu
authors.affiliation: Centre Jean Perrin, Département de Biopathologie, EA 4677 ERTICa, Université d'Auvergne, 58 rue Montalembert, 63000 Clermont-Ferrand, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Institut Régional du Cancer de Montpellier (ICM), Département de Pathologie, 208 Avenue des Apothicaires, 34298 Montpellier, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bibeau
authors.affiliation: Institut Curie, PSL Research University, Service de Pathologie, Centre de Ressources Biologiques, BRIF BB-0033-00048, 26 rue d'Ulm, 75248 Paris, France.
authors.forename: Odette
authors.initials: O
authors.lastname: Mariani
authors.affiliation: Département de Pathologie, Institut Bergonié, 229 cours de l'Argonne, CS 61283, 33076 Bordeaux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Mannina
authors.affiliation: Institut Curie, PSL Research University, Département d'Oncologie Médicale, Université Paris Descartes, 26 rue d'Ulm, 75248 Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.affiliation: Centre Léon Bérard, Département de Cancérologie Médicale, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Trédan
authors.affiliation: Centre Léon Bérard, Département de Cancérologie Médicale, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Department of Medical Oncology, Institut Bergonié Unicancer, University of Bordeaux, INSERM U916, CIC1401, 229 cours de l'Argonne, CS 61283, 33076 Bordeaux, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Bonnefoi
authors.affiliation: Institut Régional du Cancer de Montpellier (ICM), Oncologie Sénologie, 208 Avenue des Apothicaires, 34298 Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Romieu
authors.affiliation: Centre Georges-François Leclerc et CRB Ferdinand Cabanne, 1 rue du Professeur Marion, Inserm U866-UBFC, 21000 Dijon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.affiliation: Institut Gustave Roussy, Comité de Pathologie Mammaire, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.affiliation: Centre Alexis Vautrin, Département d'Oncologie Médicale, 6 Avenue de Bourgogne, 54511 Vandoeuvre Les Nancy, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Rios
authors.affiliation: Centre Antoine Lacassagne, Département d'Oncologie Médicale, 33 Avenue de Valombrose, 06189 Nice, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: Institut Paoli-Calmettes, Département d'Oncologie Médicale, 232 Boulevard de Sainte-Marguerite, 13009 Marseille, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Tarpin
authors.affiliation: Clinique Mutualiste de Bellevue, Chirurgie Gynécologique et Mammaire, 3 rue le Verrier, 42100 Saint-Etienne, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bouteille
authors.affiliation: Institut Gustave Roussy, Cancer Core Europe, 39 rue Camille Desmoulins, Villejuif 94805, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation (CRG), C/Baldiri Reixac 4, 08028 Barcelona, Spain.|Universitat Pompeu Fabra, Plaça de la Mercè, 10, 08002 Barcelona, Spain.
authors.forename: Ivo Glynne
authors.initials: IG
authors.lastname: Gut
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation (CRG), C/Baldiri Reixac 4, 08028 Barcelona, Spain.|Universitat Pompeu Fabra, Plaça de la Mercè, 10, 08002 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Sancha
authors.initials: S
authors.lastname: Martin
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.|East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Institut National du Cancer, Département de Recherche Clinique, 52 Avenue Morizet, 92513 Boulogne-Billancourt, France.
authors.forename: Iris
authors.initials: I
authors.lastname: Pauporté
authors.affiliation: INSERM U1052-CNRS 5286, Cancer Research Center of Lyon, F-69008 Lyon, France.|Université de Lyon, F-69622 Lyon, France.|Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Saintigny
authors.affiliation: Département d'Oncologie Moléculaire, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, INSERM, CNRS, Aix-Marseille Université, 232 boulevard de Sainte-Marguerite, 13009 Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Synergie Lyon Cancer, Plateforme de bioinformatique 'Gilles Thomas' Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.|Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655 Avenue de l'Europe, 38330 Montbonnot-Saint Martin, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Viari
authors.affiliation: Synergie Lyon Cancer, Plateforme de bioinformatique 'Gilles Thomas' Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D000073336:Whole Genome Sequencing
chemical_list: D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; C506487:ESR1 protein, human; C508053:ERBB2 protein, human