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 RabadanAdolfo A. Ferrando

Research output: Contribution to journalArticle

300 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)166-170
Number of pages5
JournalNature genetics
Volume46
Issue number2
DOIs
StatePublished - Feb 2014

ASJC Scopus subject areas

  • Genetics

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    Palomero, T., Couronné, L., Khiabanian, H., Kim, M. Y., Ambesi-Impiombato, A., Perez-Garcia, A., Carpenter, Z., Abate, F., Allegretta, M., Haydu, J. E., Jiang, X., Lossos, I. S., Nicolas, C., Balbin, M., Bastard, C., Bhagat, G., Piris, M. A., Campo, E., Bernard, O. A., ... Ferrando, A. A. (2014). Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nature genetics, 46(2), 166-170. https://doi.org/10.1038/ng.2873