1. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma
- Author
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Xia Zhao, Wen Xue, Zhao Wang, Jian Hou, Yang Li, Hao Ding, Zi-Min Sun, Jianfeng Zhou, Feng Zhang, Zi-Guan Zhang, Jin-Fen Wang, Sai-Juan Chen, Jing-Yi Shi, Fang-Yuan Chen, Jianda Hu, Lin-Hua Yang, Wei-Li Zhao, Jumei Shi, Jianmin Wang, Jing Lu, Yuan Hu, Zhu Chen, Lu Jiang, Li Wang, Yin-Yin Xie, Jin-Song Yan, Zhong Zheng, Zi-Xun Yan, Lan Xu, Zhaohui Gu, Ying Dong, Yuan-Hua Liu, Yang Shen, Guoyu Meng, Zhigang Peng, Chun-Ming Pan, Chang-Ping Cai, and Jinyan Huang
- Subjects
Adult ,Male ,endocrine system ,Somatic cell ,viruses ,Immunology ,DNA Mutational Analysis ,Molecular Sequence Data ,Kaplan-Meier Estimate ,Biology ,medicine.disease_cause ,Lymphoma, T-Cell ,Biochemistry ,DEAD-box RNA Helicases ,Young Adult ,Genetics ,medicine ,T-cell lymphoma ,Humans ,Exome ,Amino Acid Sequence ,Gene ,Exome sequencing ,Aged ,Aged, 80 and over ,Mutation ,Cell Cycle ,Cell Biology ,Hematology ,Middle Aged ,Uniparental Disomy ,Natural killer T cell ,medicine.disease ,Prognosis ,RNA Helicase A ,Molecular biology ,Lymphoma ,Gene expression profiling ,Cancer research ,Female ,DDX3X ,Signal Transduction - Abstract
Natural-killer/T cell lymphoma (NKTCL) is a malignant proliferation of CD56+/cytoCD3+ lymphocytes and constitutes a heterogeneous group of aggressive lymphoma prevalent in Asian and South American populations. NKTCL represents a distinct clinicopathologic entity of non-Hodgkin’s lymphoma, characterized by male predominance, strong association with Epstein-Barr virus (EBV) infection, prominent tissue necrosis and aggressive clinical course. However, molecular pathogenesis of NKTCL remains largely elusive. Here we identified somatic mutations by whole-exome sequencing in 25 NKTCL patients and extended validation through targeted sequencing in an additional 80 cases. Functional experiments including RNA unwinding test, colony forming assay, cell proliferation assay and gene expression profiling were also performed. Overall, 50.5% of NKTCL patients displayed somatic mutations of RNA helicase family, tumor suppressors (TP53 and MGA), and/or epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). Recurrent mutations were most frequently discovered in RNA helicase gene DDX3X (21/105 cases, 20.0%). Mutations of DDX3X were seldom overlapped with those of TP53. Functionally, DDX3X mutants exhibited reduced RNA unwinding activity and enhanced cell proliferation. Similar stimulatory effect on cell proliferation was observed in cells transfected with specific siRNA targeting DDX3X. Gene expression profiling revealed an association of DDX3X mutations with activation of NF-kB and MAPK pathways. The clinical follow-up data showed that DDX3X-mutated patients presented a poor prognosis. Our work suggests the heterogeneity of gene mutational spectrum of NKTCL and provides a potential therapeutic target for relevant cases. Disclosures No relevant conflicts of interest to declare.
- Published
- 2015