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: Lu Jiang, Zhao-Hui Gu, Zi-Xun Yan, Xia Zhao, Yin-Yin Xie, Zi-Guan Zhang, Chun-Ming Pan, Yuan Hu, Chang-Ping Cai, Ying Dong, Jin-Yan Huang, Li Wang, Yang Shen, Guoyu Meng, Jian-Feng Zhou, Jian-Da Hu, Jin-Fen Wang, Yuan-Hua Liu, Lin-Hua Yang, Feng Zhang, Jian-Min Wang, Zhao Wang, Zhi-Gang Peng, Fang-Yuan Chen, Zi-Min Sun, Hao Ding, Ju-Mei Shi, Jian Hou, Jin-Song Yan, Jing-Yi Shi, Lan Xu, Yang Li, Jing Lu, Zhong Zheng, Wen Xue, Wei-Li Zhao, Zhu Chen, Sai-Juan Chen
• Journal: Nature genetics (Nat Genet) Vol. 47 Issue 9 Pg. 1061-6 (Sep 2015) ISSN: 1546-1718 [Electronic] United States
• PMID: 26192917 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• DDX3X protein, human
• DEAD-box RNA Helicases

Topics

• Adult
• Aged
• Aged, 80 and over
• Amino Acid Sequence
• Cell Cycle
• DEAD-box RNA Helicases (genetics)
• DNA Mutational Analysis
• Exome
• Female
• Humans
• Kaplan-Meier Estimate
• Lymphoma, T-Cell (genetics, mortality, pathology)
• Male
• Middle Aged
• Molecular Sequence Data
• Mutation
• Prognosis
• Signal Transduction
• Uniparental Disomy (genetics)
• Young Adult