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

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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.

Author information

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.

Correspondence to Teresa Palomero or 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) doi:10.1038/ng.2873

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