TY - JOUR
T1 - Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma
AU - Dong, Gehong
AU - Liu, Xuxiang
AU - Wang, Lifu
AU - Yin, Wenjuan
AU - Bouska, Alyssa
AU - Gong, Qiang
AU - Shetty, Kunal
AU - Chen, Lu
AU - Sharma, Sunandini
AU - Zhang, Jibin
AU - Lome-Maldonado, Carmen
AU - Quintanilla-Martinez, Leticia
AU - Li, Yuping
AU - Song, Joo Y.
AU - Zhang, Wenyan
AU - Shi, Yunfei
AU - Wang, Jinhui
AU - Kong, Lingbo
AU - Wu, Xiwei
AU - Wang, Jingwen
AU - Liu, Hong gang
AU - Kong, Lingfei
AU - Sun, Wenyong
AU - Liu, Weiping
AU - Wang, Lili
AU - McKeithan, Timothy W.
AU - Iqbal, Javeed
AU - Chan, Wing C.
N1 - Funding Information:
Research reported in this publication included work performed in the Flow Cytometry core, the Integrative Genomics Core, and the Gene Editing and Viral Vector Core supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. It was also partly supported by Start-up funds from the City of Hope National Medical Center, the Dr. Norman and Melinda Payson Professorship in Hematologic Cancers and the Toni Stephenson Lymphoma Center; Beijing Natural Science Funding (No. 7132062) and Beijing Golden Bridge Engineer Seed Funding (No. 2014-37) awarded to GD. We thank Drs. Stephen Forman and Jiing Kuan Yee for kindly providing the vector epHIV7. The in vitro experiments in this study utilized cytokines from BRB Preclinical Biologics Repository at NCI.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
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U2 - 10.1038/s41375-022-01623-z
DO - 10.1038/s41375-022-01623-z
M3 - Article
C2 - 35697790
AN - SCOPUS:85131892198
SN - 0887-6924
VL - 36
SP - 2064
EP - 2075
JO - Leukemia
JF - Leukemia
IS - 8
ER -