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PMID: 24413734 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 46 ·No. 2 ·2014-02-00 ·Pages 166-70

Palomero T, Couronné L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, Carpenter Z, Abate F, Allegretta M, Haydu JE, Jiang X, Lossos IS, Nicolas C, Balbin M, Bastard C, Bhagat G, Piris MA, Campo E, Bernard OA, Rabadan R, Ferrando AA

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.

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

Chemicals

CD58 Antigens DNA-Binding Proteins DNMT3A protein, human Proto-Oncogene Proteins RHOA protein, human IDH2, 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

Authors & Affiliations

21 authors, click to expand affiliations / ORCID

Palomero Teresa

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].

Couronné Lucile

1] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2].

Khiabanian Hossein

1] Department of Systems Biology, Columbia University, New York, New York, USA. [2].

Kim Mi-Yeon