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LYMPHOMA

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

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.

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Fig. 1: Patient cohort and clinical information.
Fig. 2: Mutations identified in 209 ENKTCL cases.
Fig. 3: Frequency of gCNAs in 209 ENKTCLs and comparison between two ethnic groups.
Fig. 4: Genetic clusters identified using NMF consensus clustering.
Fig. 5: Cooperation between PRDM1 loss and STAT3 mutation in promoting NK-cells growth.

Data availability

The NGS data are deposited in the National Center for Biotechnology Information (NCBI) database of Genotypes and Phenotypes (dbGaP) under the accession number phs002925.v1.p1.

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Acknowledgements

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.

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Contributions

GD, XL, and WCC conceived and designed the project and wrote the manuscript; GD, LW, WY, JW, HL, LK, WS, WZ, and WL contributed the Asian ENKTCL cases and collected the clinical information. GD performed the DNA extraction and coordinate sequencing studies. QG, AB, SS, JZ, TM, LW and JI performed data management data extraction and analysis; LC performed statistical analysis. JW and XW did the sequencing experiment. CLM, LQM, and JYS contributed ENKTCL case specimens and clinical information from their institutions. XL and KS performed the in vitro functional study. YS, LK, and YL performed experiments and prepared figures and assisted in manuscript preparation. JI and WCC finalized the manuscript.

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Correspondence to Javeed Iqbal or Wing C. Chan.

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Written informed consent was obtained from all patients. The institutional review boards (IRBs) of the respective institutions approved this study.

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Dong, G., Liu, X., Wang, L. et al. Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma. Leukemia (2022). https://doi.org/10.1038/s41375-022-01623-z

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