title: A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma.
abstract: The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly17Val) using exome and transcriptome sequencing of samples from individuals with AITL. Further examination of the RHOA mutation encoding p.Gly17Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma. We demonstrate that the RHOA mutation encoding p.Gly17Val, which was found in 53.3% (24 of 45) of the AITL cases examined, is oncogenic in nature using multiple molecular assays. Molecular modeling and docking simulations provided a structural basis for the loss of GTPase activity in the RHOA Gly17Val mutant. Our experimental data and modeling results suggest that the RHOA mutation encoding p.Gly17Val is a driver mutation in AITL. On the basis of these data and through integrated pathway analysis, we build a comprehensive signaling network for AITL oncogenesis.
authors.affiliation: 1] Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea. [2] Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea. [3].
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Yoo
authors.affiliation: 1] Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea. [2].
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Sung
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: 1] Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea. [2] Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Sangok
authors.initials: S
authors.lastname: Kim
authors.affiliation: 1] Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea. [2] Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Haeseung
authors.initials: H
authors.lastname: Lee
authors.affiliation: Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Seongjin
authors.initials: S
authors.lastname: Park
authors.affiliation: Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Sang Cheol
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Byungwook
authors.initials: B
authors.lastname: Lee
authors.affiliation: DNA Link, Inc., Seoul, Korea.
authors.forename: Kyoohyoung
authors.initials: K
authors.lastname: Rho
authors.affiliation: DNA Link, Inc., Seoul, Korea.
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: School of Systems Biomedical Science, Soongsil University, Seoul, Korea.
authors.forename: Kwang-Hwi
authors.initials: KH
authors.lastname: Cho
authors.affiliation: 1] Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea. [2] Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Wankyu
authors.initials: W
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Ju
authors.affiliation: 1] Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea. [2] Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Jaesang
authors.initials: J
authors.lastname: Kim
authors.affiliation: 1] Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea. [2] Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: 1] Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea. [2] Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.affiliation: 1] Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea. [2] Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Sanghyuk
authors.initials: S
authors.lastname: Lee
authors.affiliation: 1] Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea. [2] Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Young Hyeh
authors.initials: YH
authors.lastname: Ko
mesh_terms: D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D059472:Exome / Q000235:genetics; D020868:Gene Silencing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein