Abstract
DDX3X loss-of-function mutations contribute to natural killer/T-cell lymphoma (NKTCL) pathogenesis.
Major finding: DDX3X loss-of-function mutations contribute to natural killer/T-cell lymphoma (NKTCL) pathogenesis.
Approach: Somatic mutations in NKTCL were identified by whole-exome sequencing and confirmed by targeted sequencing.
Impact: Mutations in DDX3X and TP53 are associated with poor clinical outcome in patients with NKTCL.
Natural killer/T-cell lymphoma (NKTCL) is an aggressive subtype of non-Hodgkin lymphoma that has poor prognosis and no available targeted therapy. Mutations in TP53, NRAS, and genes in the JAK–STAT pathway have been identified in NKTCL, but the role of these and other as-yet-unidentified driver mutations in the molecular pathogenesis of NKTCL has not been fully elucidated. To identify additional genetic alterations that may drive NKTCL tumorigenesis, Jiang and colleagues performed whole-exome sequencing of matched tumor and normal samples from 25 patients with NKTCL and identified mutations in 795 genes that were predicted to alter protein function. Based on the presence of recurrent mutations predicted to modulate functions and relevance to oncogenesis, 26 of the 795 genes were selected for validation in 80 patients with NKTCL. The RNA helicase gene DEAD box helicase 3, X-linked (DDX3X), mutated in 21 (20%) of 105 patients, was found to be the most frequently mutated gene. In addition, mutations in six other members of the same RNA helicase family as well as known tumor suppressors (TP53), the JAK–STAT pathway (STAT3), and epigenetic modifiers (MLL2) were also identified. There was little overlap between DDX3X mutations and TP53 mutations. Most of the identified alterations in DDX3X affected conserved amino acids in the ATP-binding helicase and the C-terminal helicase domains, and several of these mutations exhibited decreased RNA unwinding activity in vitro. Furthermore, wild-type DDX3X exerted a suppressive effect on cell-cycle progression and activation of the NF-κB and MAPK pathways, which was lost upon mutation of DDX3X. Kaplan-Meier analysis of prognostic data for 95 patients with NKTCL showed that high-risk NKTCL patients with mutant DDX3X and/or mutant TP53 had significantly worse prognosis compared with patients lacking mutations in both DDX3X and TP53. Together, these results identify DDX3X loss-of-function mutations in NKTCL and demonstrate their role in NKTCL pathogenesis.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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