Abstract
Extranodal natural killer T-cell lymphoma (nasal type; NKTCL) is an aggressive malignancy strongly associated with Epstein-Barr virus (EBV) infection. However, the role of EBV in NKTCL development is unclear, largely due to the lack of information about EBV genome and transcriptome in NKTCL. Here, using high-throughput sequencing, we obtained whole genome (n = 27) and transcriptome datasets (n = 18) of EBV derived from NKTCL tumor biopsies. We assembled 27 EBV genomes and detected an average of 1,152 single nucleotide variants and 44.8 indels (<50 bp) of EBV per sample. We also identified frequent focal EBV genome deletions and integrated EBV fragments in the host genome. Moreover, Phylogenetic analysis revealed that NKTCL-derived EBVs are closely clustered; transcriptome analysis revealed less activation of both latent and lytic genes and larger amount of T-cell epitope alterations in NKTCL, as compared with other EBV-associated cancers. Furthermore, we observed transcriptional defects of the BARTs miRNA by deletion, and the disruption of host NHEJ1 by integrated EBV fragment, implying novel pathogenic mechanisms of EBV. Taken together, we reported for the first time global mutational and transcriptional profiles of EBV in NKTCL clinical samples, revealing important somatic events of EBV and providing insights to better understanding of EBV’s contribution in tumorigenesis.
Highlights
IntroductionExtranodal natural killer T-cell lymphoma (NKTCL, nasal type) is an aggressive form of lymphoma with geographical prevalence in Asian and South Americanpopulations [1,2,3]
Extranodal natural killer T-cell lymphoma (NKTCL, nasal type) is an aggressive form of lymphoma with geographical prevalence in Asian and South AmericanSchool of Medicine, Sun Yat-Sen University, Guangzhou 510080, China 5 RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China 6 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Division of Medical Oncology, National Cancer Center Singapore, Singapore, Singapore 8 SingHealth Duke-NUS Blood Cancer Centre, Singapore, Singapore 9 Duke-NUS Medical School, Singapore, Singapore Genome Institute of Singapore, A*STAR, Singapore, Singapore Center for Precision Medicine, Sun Yat-Sen University, Guangzhou, China R-J Peng et al.populations [1,2,3]
Epstein-Barr virus (EBV) sequences were assembled into several large contiguous DNA sequences, which were aligned to the EBV reference genome
Summary
Extranodal natural killer T-cell lymphoma (NKTCL, nasal type) is an aggressive form of lymphoma with geographical prevalence in Asian and South Americanpopulations [1,2,3]. Multiple factors have been implicated in the development of NKTCL. Our recent genome-wide association study identified HLA-DPB1 as a susceptibility gene predisposing individuals to NKTCL [4]. Acquired somatic alterations, including DDX3X, TP53, and STAT3 mutations have been determined in NKTCL tumors and the related signaling pathways, such as JAK-STAT, NFκB, and MAPK pathways have been implicated in its pathogenesis [5, 6]. Epstein-Barr virus (EBV) has been strongly associated with NKTCL, mostly based on the observation of EBV molecules in the tumor tissue, and the correlations between EBV load and disease diagnosis as well as prognosis [1, 2, 7]. Environmental factors such as exposures to chemical solvents increased risk of NKTCL [3]
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