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

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

Author information

  • 11] 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].
  • 21] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2].
  • 31] Department of Systems Biology, Columbia University, New York, New York, USA. [2].
  • 4Institute for Cancer Genetics, Columbia University, New York, New York, USA.
  • 5Department of Systems Biology, Columbia University, New York, New York, USA.
  • 61] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Control and Computer Engineering, Politecnico di Torino, Torino, Italy.
  • 7Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
  • 81] Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida, USA. [2] Department of Molecular and Cellular Pharmacology, University of Miami, Miami, Florida, USA.
  • 9Hematology Service, Hospital Central de Asturias, Oviedo, Spain.
  • 10Molecular Oncology Laboratory, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain.
  • 11INSERM U918, Rouen University, Centre Henri Becquerel, Rouen, France.
  • 12Department of Pathology, Columbia University Medical Center, New York, New York, USA.
  • 131] Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain. [2] Instituto de Formacion e Investigacion Marques de Valdecilla-IFIMAV, Santander, Spain.
  • 141] Hematopathology Section, Department of Pathology, Hospital Clinic, Barcelona, Spain. [2] Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
  • 151] INSERM U985, Villejuif, France. [2] Université Paris-Sud, Orsay, France. [3] Institut Gustave Roussy, Villejuif, France.
  • 161] Department of Systems Biology, Columbia University, New York, New York, USA. [2] Department of Biomedical Informatics, Columbia University, New York, New York, USA.
  • 171] 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.

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.

PMID:
24413734
[PubMed - indexed for MEDLINE]
PMCID:
PMC3963408
Free PMC Article
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