title: Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas.
abstract: Peripheral T cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non-Hodgkin lymphomas. Here we combined whole-exome sequencing of 12 tumor-normal DNA pairs, RNA sequencing analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA mutation encoding a p.Gly17Val alteration present in 22 of 35 (67%) angioimmunoblastic T cell lymphoma (AITL) samples and in 8 of 44 (18%) PTCL, not otherwise specified (PTCL-NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated guanine-exchange factor (GEF) proteins. In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.
authors.affiliation: 1] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2] Department of Pathology, Columbia University Medical Center, New York, New York, USA. [3].
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.affiliation: 1] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2].
authors.forename: Lucile
authors.initials: L
authors.lastname: Couronné
authors.affiliation: 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2].
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiombato
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Arianne
authors.initials: A
authors.lastname: Perez-Garcia
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Carpenter
authors.affiliation: 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Control and Computer Engineering, Politecnico di Torino, Torino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Abate
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Allegretta
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: J Erika
authors.initials: JE
authors.lastname: Haydu
authors.affiliation: Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.affiliation: 1] Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida, USA. [2] Department of Molecular and Cellular Pharmacology, University of Miami, Miami, Florida, USA.
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.affiliation: Hematology Service, Hospital Central de Asturias, Oviedo, Spain.
authors.forename: Concha
authors.initials: C
authors.lastname: Nicolas
authors.affiliation: Molecular Oncology Laboratory, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Milagros
authors.initials: M
authors.lastname: Balbin
authors.affiliation: INSERM U918, Rouen University, Centre Henri Becquerel, Rouen, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bastard
authors.affiliation: Department of Pathology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: 1] Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain. [2] Instituto de Formacion e Investigacion Marques de Valdecilla-IFIMAV, Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: 1] Hematopathology Section, Department of Pathology, Hospital Clinic, Barcelona, Spain. [2] Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors.forename: Elias
authors.identifier: 0000000198509793
authors.initials: E
authors.lastname: Campo
authors.affiliation: 1] INSERM U985, Villejuif, France. [2] Université Paris-Sud, Orsay, France. [3] Institut Gustave Roussy, Villejuif, France.
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.affiliation: 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Biomedical Informatics, Columbia University, New York, New York, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: 1] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2] Department of Pathology, Columbia University Medical Center, New York, New York, USA. [3] Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001483:Base Sequence; D018968:CD58 Antigens / Q000235:genetics; D019295:Computational Biology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D044127:Epigenesis, Genetic / Q000235:genetics*; D004926:Escherichia coli; D059472:Exome / Q000235:genetics; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics*; D017423:Sequence Analysis, RNA; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D018968:CD58 Antigens; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; C066737:RHOA protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D020742:rhoA GTP-Binding Protein