STAT Transcription Factors; Janus Kinases; Adult; Aged; Aged, 80 and over; Breast Implants/adverse effects; DNA Copy Number Variations; Female; Genome, Human; Humans; Janus Kinases/metabolism; Lymphoma, Large-Cell, Anaplastic/etiology; Lymphoma, Large-Cell, Anaplastic/genetics; Lymphoma, Large-Cell, Anaplastic/pathology; Middle Aged; Mutation/genetics; STAT Transcription Factors/metabolism; Epigenesis, Genetic; Signal Transduction; Breast Implants; Lymphoma, Large-Cell, Anaplastic; Mutation; Biochemistry; Immunology; Hematology; Cell Biology
Abstract :
[en] The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
Disciplines :
Hematology
Author, co-author :
Laurent, Camille ; Pathology and Cytology Department, Centre Hospitalo-Universitaire de Toulouse,Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France ; Centre de Recherche en Cancerologie de Toulouse, INSERM, UMR1037 laboratoire d'excellence Toulouse Cancer (Labex TOUCAN), Paul Sabatier University Toulouse III, Toulouse, France
Nicolae, Alina; Pathology and Cytology Department, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France ; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France
Laurent, Cécile ; Institut Carnot CALYM, Lymphoma Academic Research Organisation, Institut Carnot, Pierre-Bénite, France
Le Bras, Fabien; Lymphoid Malignancies Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, France
Haioun, Corinne; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France ; Lymphoid Malignancies Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, France
Fataccioli, Virginie; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France ; Department of Pathology, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
Amara, Nadia; Pathology and Cytology Department, Centre Hospitalo-Universitaire de Toulouse,Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
Adélaïde, José; Department of Predictive Oncology, Institut Paoli-Calmettes, and ; Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique UMR7258, Aix-Marseille University, UM105, Marseille, France
Guille, Arnaud; Department of Predictive Oncology, Institut Paoli-Calmettes, and ; Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique UMR7258, Aix-Marseille University, UM105, Marseille, France
Schiano, Jean-Marc; Department of Hematology, Institut Paoli-Calmettes, Marseille, France
Tesson, Bruno; Institut Carnot CALYM, Lymphoma Academic Research Organisation, Institut Carnot, Pierre-Bénite, France
Traverse-Glehen, Alexandra; Pathology Department, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France
Chenard, Marie-Pierre; Pathology and Cytology Department, Centre Hospitalier Universitaire Hautepierre, Strasbourg, France
Mescam, Lénaïg; Department of Bio-Pathology Institut Paoli-Calmettes, Marseille, France
Moreau, Anne; Pathology and Cytology Department, Centre Hospitalier Hôtel Dieu, Nantes, France
Chassagne-Clement, Catherine; Department of Bio-Pathology Pathology and Cytology Department, Centre Léon Bérard, Lyon, France
Somja, Joan ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Escudié, Frédéric; Pathology and Cytology Department, Centre Hospitalo-Universitaire de Toulouse,Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
André, Marc; Department of Hematology, Centre Hospitalo-Universitaire UCLouvain Namur, Yvoir, Belgium
Martin, Nadine; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France
Lacroix, Laetitia; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France
Lemonnier, François; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France ; Lymphoid Malignancies Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, France
Hamy, Anne-Sophie; Curie Institute, Residual Tumour and Response to Treatment Laboratory, RT2Lab, INSERM, U 932 Immunity and Cancer, Paris, France
Reyal, Fabien; Curie Institute, Residual Tumour and Response to Treatment Laboratory, RT2Lab, INSERM, U 932 Immunity and Cancer, Paris, France ; Curie Institute, Department of Surgery, Paris Descartes University, Paris, France
Bannier, Marie; Department of Surgery, Institut Paoli-Calmettes, Marseille, France
Oberic, Lucie; Hematology Department and
Prade, Nais; Laboratory of Hematology, Centre Hospitalo-Universitaire de Toulouse, Institut Universitaire de Cancérologie de Toulouse, Toulouse, France, and
Frénois, François-Xavier; Pathology and Cytology Department, Centre Hospitalo-Universitaire de Toulouse,Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
Beldi-Ferchiou, Asma ; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France ; Department of Immunobiology and Haematobiology, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
Delfau-Larue, Marie-Helene ; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France ; Department of Immunobiology and Haematobiology, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
Bouabdallah, Reda; Department of Hematology, Institut Paoli-Calmettes, Marseille, France
Birnbaum, Daniel; Department of Predictive Oncology, Institut Paoli-Calmettes, and ; Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique UMR7258, Aix-Marseille University, UM105, Marseille, France
Brousset, Pierre; Pathology and Cytology Department, Centre Hospitalo-Universitaire de Toulouse,Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France ; Centre de Recherche en Cancerologie de Toulouse, INSERM, UMR1037 laboratoire d'excellence Toulouse Cancer (Labex TOUCAN), Paul Sabatier University Toulouse III, Toulouse, France
Xerri, Luc; Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique UMR7258, Aix-Marseille University, UM105, Marseille, France ; Department of Bio-Pathology Institut Paoli-Calmettes, Marseille, France
Gaulard, Philippe ; Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France ; Department of Pathology, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France
This work was supported in part by institutional grants from the Institut National du Cancer (INCA, 2017-007), the Fondation pour la Recherche Médicale (FRM, Equipe Labellisée DEQ20160334875), the Leukemia Lymphoma Society (LLS SCOR 7013-17), the Laboratoire d’Excellence Toulouse Cancer (TOUCAN, contract ANR11-LABX), the Programme Hospitalo-Universitaire en Cancérologie CAPTOR (contract ANR11-PHUC0001), the Lymphome Study Association (LYSA), and the Institut Carnot Lymphome (CALYM).
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