title: Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.
abstract: Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Zi-Xun
authors.initials: ZX
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Yin-Yin
authors.initials: YY
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Zi-Guan
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Pan
authors.affiliation: Department of Otorhinolaryngology, Rui Jin Hospital, SJTU School of Medicine, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Otorhinolaryngology, Rui Jin Hospital, SJTU School of Medicine, Shanghai, China.
authors.forename: Chang-Ping
authors.initials: CP
authors.lastname: Cai
authors.affiliation: Department of Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Jin-Yan
authors.initials: JY
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Meng
authors.affiliation: Department of Hematology, Tongji Medical College, Huazhong University of Science and Technology, Tongji Hospital, Wuhan, China.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Zhou
authors.affiliation: Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
authors.forename: Jian-Da
authors.initials: JD
authors.lastname: Hu
authors.affiliation: Department of Pathology, Shanxi Oncology Hospital, Taiyuan, China.
authors.forename: Jin-Fen
authors.initials: JF
authors.lastname: Wang
authors.affiliation: Department of Oncology, Jiangsu Cancer Hospital, Nanjing, China.
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Department of Hematology, Second Affiliated Hospital of Shanxi Medical University, Taiyuan, China.
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Yang
authors.affiliation: Department of Hematology, Anhui Oncology Hospital, Bengbu Medical College, Bengbu, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Wang
authors.affiliation: Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Hematology, First Affiliated Hospital of Guangxi Medical University, Nanning, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Peng
authors.affiliation: Department of Hematology, Renji Hospital, SJTU School of Medicine, Shanghai, China.
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Chen
authors.affiliation: Department of Hematology, Anhui Provincial Hospital, Hefei, China.
authors.forename: Zi-Min
authors.initials: ZM
authors.lastname: Sun
authors.affiliation: Department of Radiation Oncology, Eye and ENT Hospital of Fudan University, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ju-Mei
authors.initials: JM
authors.lastname: Shi
authors.affiliation: Department of Hematology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Hematology, Second Hospital of Dalian Medical University, Dalian, China.
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.|Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.|Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, Shanghai, China.|Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002453:Cell Cycle; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011379:Prognosis; D015398:Signal Transduction; D024182:Uniparental Disomy / Q000235:genetics; D055815:Young Adult
chemical_list: C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases