title: Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.
abstract: Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas.
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
authors.forename: David
authors.identifier: 0000-0003-0703-6762
authors.initials: D
authors.lastname: Vallois
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland;
authors.forename: Maria Pamela D
authors.initials: MP
authors.lastname: Dobay
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada; Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada;
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.affiliation: INSERM U955, Université Paris-Est, Département de Pathologie, Hôpital Henri-Mondor, Créteil, France;
authors.forename: François
authors.initials: F
authors.lastname: Lemonnier
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.affiliation: Department of Biochemistry, University of Lausanne, Lausanne, Switzerland;
authors.forename: Mélanie
authors.initials: M
authors.lastname: Juilland
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland;
authors.forename: Justyna
authors.initials: J
authors.lastname: Iwaszkiewicz
authors.affiliation: INSERM U955, Université Paris-Est, Département de Pathologie, Hôpital Henri-Mondor, Créteil, France;
authors.forename: Virginie
authors.initials: V
authors.lastname: Fataccioli
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
authors.forename: Bettina
authors.initials: B
authors.lastname: Bisig
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
authors.forename: Annalisa
authors.initials: A
authors.lastname: Roberti
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Jasleen
authors.initials: J
authors.lastname: Grewal
authors.affiliation: Service d'Anatomie et cytologie pathologiques, Hôpital Necker, Paris, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Bruneau
authors.affiliation: Service d'Anatomie et cytologie pathologiques, Hôpital Saint-Antoine, Paris, France;
authors.forename: Bettina
authors.initials: B
authors.lastname: Fabiani
authors.affiliation: Service d'Anatomie pathologique, Hôpital Avicenne, Bobigny, France;
authors.forename: Antoine
authors.initials: A
authors.lastname: Martin
authors.affiliation: Hématologie clinique, CHU Liège, Liège, Belgium;
authors.forename: Christophe
authors.initials: C
authors.lastname: Bonnet
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.affiliation: Service de Biostatistiques, GH Necker-Enfants Malades, Paris, France;
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jais
authors.affiliation: Plate-forme de Génomique Fonctionnelle et Structurale, Institut Pour la Recherche sur le Cancer de Lille, Lille, France;
authors.forename: Martin
authors.initials: M
authors.lastname: Figeac
authors.affiliation: INSERM U1170, Institut Gustave Roussy, Villejuif, France;
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.affiliation: SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland;
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Hémopathies lymphoides, CHU Henri Mondor, Creteil, France;
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.affiliation: Hématologie Clinique, CHU Estaing, Clermont-Ferrand, France; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Tournilhac
authors.affiliation: Department of Biochemistry, University of Lausanne, Lausanne, Switzerland;
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: INSERM U955, Université Paris-Est, Département de Pathologie, Hôpital Henri-Mondor, Créteil, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
authors.forename: Laurence
authors.initials: L
authors.lastname: de Leval
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D015331:Cohort Studies; D005500:Follow-Up Studies; D019672:Genes, T-Cell Receptor / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007119:Immunoblastic Lymphadenopathy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein