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: 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
• Journal: Nature genetics (Nat Genet) Vol. 46 Issue 2 Pg. 166-70 (Feb 2014) ISSN: 1546-1718 [Electronic] United States
• PMID: 24413734 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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)