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Nat Genet. 2014 Apr;46(4):371-5. doi: 10.1038/ng.2916. Epub 2014 Mar 2.

A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma.

Author information

1
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].
2
1] Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea. [2].
3
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
4
1] Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea. [2] Department of Life Science, Ewha Womans University, Seoul, Korea.
5
Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
6
DNA Link, Inc., Seoul, Korea.
7
School of Systems Biomedical Science, Soongsil University, Seoul, Korea.
8
Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
9
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.
10
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.

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.

PMID:
24584070
DOI:
10.1038/ng.2916
[Indexed for MEDLINE]

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