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

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 Internation...

Full description

Saved in:
Bibliographic Details
Published inLeukemia Vol. 36; no. 8; pp. 2064 - 2075
Main Authors Dong, Gehong, Liu, Xuxiang, Wang, Lifu, Yin, Wenjuan, Bouska, Alyssa, Gong, Qiang, Shetty, Kunal, Chen, Lu, Sharma, Sunandini, Zhang, Jibin, Lome-Maldonado, Carmen, Quintanilla-Martinez, Leticia, Li, Yuping, Song, Joo Y, Zhang, Wenyan, Shi, Yunfei, Wang, Jinhui, Kong, Lingbo, Wu, Xiwei, Wang, Jingwen, Liu, Hong-Gang, Kong, Lingfei, Sun, Wenyong, Liu, Weiping, Wang, Lili, McKeithan, Timothy W, Iqbal, Javeed, Chan, Wing C
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.08.2022
Subjects
Cell survival
Clustering
Copy number
Epstein-Barr virus
Gene regulation
Genes
Genetic analysis
Genomic analysis
Lymphadenopathy
Lymphocytes T
Lymphoma
Minority & ethnic groups
Mutation
Natural killer cells
Risk groups
Stat3 protein
Survival
T-cell lymphoma
Tumor suppressor genes
Tumors
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
AUTHOR CONTRIBUTIONS
These authors contributed equally to this work
G.D., X.L. and W.C.C. conceived and designed the project and wrote the manuscript; G.D., L.W., W.Y., J.W., H.L., L.K., W.S., W.Z., and W.L. contributed the Asian ENKTCL cases and collected the clinical information. G.D. performed the DNA extraction and coordinate sequencing studies. Q.G., A.B., S.S., J.Z., T.M., L.W. and J.I. performed data management data extraction and analysis; L.C. performed statistical analysis. J.W. and X.W. did the sequencing experiment. C.L.M., L.Q.M., and J.S. contributed ENKTCL case specimens and clinical information from their institutions. X.L. and K.S. performed the in vitro functional study. Y.S., L.K. and Y.L. performed experiments and prepared figures and assisted in manuscript preparation. J.I. and W.C.C. finalized the manuscript.
ISSN:0887-6924
1476-5551
1476-5551
DOI:10.1038/s41375-022-01623-z