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

Nature Genetics volume 46, pages 166–170 (2014)Cite this article

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Abstract

Peripheral T cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non-Hodgkin lymphomas1,2. 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.

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Figure 1: RHOA mutations in PTCL.
Figure 2: Functional characterization of the RHOA Gly17Val protein.
Figure 3: DNMT3A, TET2, IDH2, FYN, ATM, TET3, B2M and CD58 alterations in PTCL.
Figure 4: Structural modeling and functional characterization of the FYN mutations identified in PTCL.

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Acknowledgements

We would like to thank V. Ribrag (Institut Gustave Roussy) for providing a PTCL sample and R. Parsons (Mount Sinai School of Medicine) for assistance in the setup of RHOA GTP-loading assays. This work was supported by a Leukemia and Lymphoma Society Translational Research Grant (A.A.F.), a Herbert Irving Comprehensive Cancer Center interprogrammatic pilot project grant (A.A.F. and R.R.), a US National Institutes of Health Ruth L. Kirschstein National Research Service Award (1F30CA174099 to J.E.H.), a grant from the Ligue Nationale Contre le Cancer (O.A.B.) and an Institut National du Cancer (INCa)/–Direction de l'Hospitalisation et de l'Organisation des soins (DHOS) translational research grant (O.A.B.). L.C. is funded by ITMO (Institut Multi-Organismes Cancer) and INCa. M.-Y.K. is funded by the Leukemia and Lymphoma Society. E.C. is supported by the Spanish Ministry of Science and Innovation (SAF2012-38432) and Institucio Catalana de Recerca i Estudis Avancats.

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Author notes

  1. Teresa Palomero, Lucile Couronné and Hossein Khiabanian: These authors contributed equally to this work.

Authors and Affiliations

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

    Teresa Palomero, Lucile Couronné, Mi-Yeon Kim, Alberto Ambesi-Impiombato, Arianne Perez-Garcia, Maddalena Allegretta, J Erika Haydu & Adolfo A Ferrando

  2. Department of Pathology, Columbia University Medical Center, New York, New York, USA

    Teresa Palomero, Govind Bhagat & Adolfo A Ferrando

  3. Department of Systems Biology, Columbia University, New York, New York, USA

    Hossein Khiabanian, Zachary Carpenter, Francesco Abate & Raul Rabadan

  4. Department of Control and Computer Engineering, Politecnico di Torino, Torino, Italy

    Francesco Abate

  5. Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida, USA

    Xiaoyu Jiang & Izidore S Lossos

  6. Department of Molecular and Cellular Pharmacology, University of Miami, Miami, Florida, USA

    Izidore S Lossos

  7. Hematology Service, Hospital Central de Asturias, Oviedo, Spain

    Concha Nicolas

  8. Molecular Oncology Laboratory, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain

    Milagros Balbin

  9. INSERM U918, Rouen University, Centre Henri Becquerel, Rouen, France

    Christian Bastard

  10. Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain

    Miguel A Piris

  11. Instituto de Formacion e Investigacion Marques de Valdecilla-IFIMAV, Santander, Spain

    Miguel A Piris

  12. Department of Pathology, Hematopathology Section, Hospital Clinic, Barcelona, Spain

    Elias Campo

  13. Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain

    Elias Campo

  14. INSERM U985, Villejuif, France

    Olivier A Bernard

  15. Université Paris–Sud, Orsay, France

    Olivier A Bernard

  16. Institut Gustave Roussy, Villejuif, France

    Olivier A Bernard

  17. Department of Biomedical Informatics, Columbia University, New York, New York, USA

    Raul Rabadan

  18. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA

    Adolfo A Ferrando

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  1. Teresa Palomero
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Contributions

T.P. directed and supervised mutation analysis, performed functional assays and wrote the manuscript. L.C. performed validation and recurrence mutation analysis and functional assays. H.K. performed exome and RNA-seq mutation analysis. M.-Y.K. performed peptide binding assays. A.A.-I. analyzed Illumina deep sequencing amplicon sequencing data. A.P.-G. performed functional assays. Z.C. performed structure-function analysis and analyzed Illumina sequence data. F.A. performed RNA-seq mutation analysis and fusion oncogene identification. M.A. performed validation analysis of Illumina sequencing results. J.E.H. performed functional assays. X.J. performed functional assays. I.S.L. contributed clinical samples and supervised functional assays. C.N., M.B., C.B., G.B., M.A.P. and E.C. contributed clinical samples. O.A.B. designed the study, contributed samples and supervised research. R.R. directed and supervised the analysis of Illumina sequencing data. A.A.F. designed the study, directed and supervised research and wrote the manuscript.

Corresponding authors

Correspondence to Teresa Palomero, Raul Rabadan or Adolfo A Ferrando.

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The authors declare no competing financial interests.

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Palomero, T., Couronné, L., Khiabanian, H. et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 46, 166–170 (2014). https://doi.org/10.1038/ng.2873

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