Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas

Teresa Palomero; Lucile Couronné; Hossein Khiabanian; Mi-Yeon Kim; Alberto Ambesi-Impiombato; Arianne Perez-Garcia; Zachary Carpenter; Francesco Abate; Maddalena Allegretta; J Erika Haydu; Xiaoyu Jiang; Izidore S Lossos; Concha Nicolas; Milagros Balbin; Christian Bastard; Govind Bhagat; Miguel A Piris; Elias Campo; Olivier A Bernard; Raul Rabadan; Adolfo A Ferrando

doi:10.1038/ng.2873

Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas

Nat Genet. 2014 Feb;46(2):166-70. doi: 10.1038/ng.2873. Epub 2014 Jan 12.

Authors

Teresa Palomero¹, Lucile Couronné², Hossein Khiabanian³, Mi-Yeon Kim⁴, Alberto Ambesi-Impiombato⁴, Arianne Perez-Garcia⁴, Zachary Carpenter⁵, Francesco Abate⁶, Maddalena Allegretta⁴, J Erika Haydu⁴, Xiaoyu Jiang⁷, Izidore S Lossos⁸, Concha Nicolas⁹, Milagros Balbin¹⁰, Christian Bastard¹¹, Govind Bhagat¹², Miguel A Piris¹³, Elias Campo¹⁴, Olivier A Bernard¹⁵, Raul Rabadan¹⁶, Adolfo A Ferrando¹⁷

Affiliations

¹ 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].
² 1] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2].
³ 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2].
⁴ Institute for Cancer Genetics, Columbia University, New York, New York, USA.
⁵ Department of Systems Biology, Columbia University, New York, New York, USA.
⁶ 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Control and Computer Engineering, Politecnico di Torino, Torino, Italy.
⁷ Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
⁸ 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.
⁹ Hematology Service, Hospital Central de Asturias, Oviedo, Spain.
¹⁰ Molecular Oncology Laboratory, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
¹¹ INSERM U918, Rouen University, Centre Henri Becquerel, Rouen, France.
¹² Department of Pathology, Columbia University Medical Center, New York, New York, USA.
¹³ 1] Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain. [2] Instituto de Formacion e Investigacion Marques de Valdecilla-IFIMAV, Santander, Spain.
¹⁴ 1] Hematopathology Section, Department of Pathology, Hospital Clinic, Barcelona, Spain. [2] Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
¹⁵ 1] INSERM U985, Villejuif, France. [2] Université Paris-Sud, Orsay, France. [3] Institut Gustave Roussy, Villejuif, France.
¹⁶ 1] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Biomedical Informatics, Columbia University, New York, New York, USA.
¹⁷ 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.

PMID: 24413734
PMCID: PMC3963408
DOI: 10.1038/ng.2873

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Ataxia Telangiectasia Mutated Proteins / genetics
Base Sequence
CD58 Antigens / genetics
Computational Biology
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA Methyltransferase 3A
DNA-Binding Proteins / genetics
Dioxygenases
Epigenesis, Genetic / genetics*
Escherichia coli
Exome / genetics
Fluorescent Antibody Technique
HEK293 Cells
High-Throughput Nucleotide Sequencing
Humans
Isocitrate Dehydrogenase / genetics
Lymphoma, T-Cell, Peripheral / genetics*
Molecular Sequence Data
Mutation, Missense / genetics
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins c-fyn / genetics*
Sequence Analysis, RNA
rhoA GTP-Binding Protein / genetics*

Substances

CD58 Antigens
DNA-Binding Proteins
DNMT3A protein, human
Proto-Oncogene Proteins
RHOA protein, human
IDH2 protein, human
Isocitrate Dehydrogenase
Dioxygenases
TET2 protein, human
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A
FYN protein, human
Proto-Oncogene Proteins c-fyn
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
rhoA GTP-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding