Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma

Gehong Dong, Xuxiang Liu, Lifu Wang, Wenjuan Yin, Alyssa Bouska, Qiang Gong, Kunal Shetty, Lu Chen, Sunandini Sharma, Jibin Zhang, Carmen Lome-Maldonado, Leticia Quintanilla-Martinez, Yuping Li, Joo Y. Song, Wenyan Zhang, Yunfei Shi, Jinhui Wang, Lingbo Kong, Xiwei Wu, Jingwen WangHong gang Liu, Lingfei Kong, Wenyong Sun, Weiping Liu, Lili Wang, Timothy W. McKeithan, Javeed Iqbal, Wing C. Chan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Extra-nodal NK/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive Epstein-Barr virus associated lymphoma, typically presenting in the nasal and paranasal areas. We assembled a large series of ENKTCL (n = 209) for comprehensive genomic analysis and correlative clinical study. The International Lymphoma Prognostic Index (IPI), site of disease, stage, lymphadenopathy, and hepatomegaly were associated with overall survival. Genetic analysis revealed frequent oncogenic activation of the JAK/STAT3 pathway and alterations in tumor suppressor genes (TSGs) and genes associated with epigenomic regulation. Integrated genomic analysis including recurrent mutations and genomic copy number alterations using consensus clustering identified seven distinct genetic clusters that were associated with different clinical outcomes, thus constituting previously unrecognized risk groups. The genetic profiles of ENTKCLs from Asian and Hispanic ethnic groups showed striking similarity, indicating shared pathogenetic mechanism and tumor evolution. Interestingly, we discovered a novel functional cooperation between activating STAT3 mutations and loss of the TSG, PRDM1, in promoting NK-cell growth and survival. This study provides a genetic roadmap for further analysis and facilitates investigation of actionable therapeutic opportunities in this aggressive lymphoma.

Original languageEnglish (US)
Pages (from-to)2064-2075
Number of pages12
JournalLeukemia
Volume36
Issue number8
DOIs
StatePublished - Aug 2022

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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