Abstract
SummaryEpstein-Barr virus (EBV) T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells, including chronic active EBV infection of T/NK-cell type (CAEBV+T/NK), EBV-associated hemophagocytic lymphohistiocytosis (EBV+HLH), extranodal NK/T-cell lymphoma of nasal type (ENKTL), and aggressive NK-cell leukemia (ANKL). However, the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown. A total of 171 nonimmunosuppressed patients with EBV+T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed. The 94 gene variants, mostly located in UNC13D, LYST, ITK, and PRF1 genes were detected, and mutations covered 28/50 (56.00%) of CAEBV-T/NK, 31/51 (60.78%) of EBV+HLH, 13/28 (46.42%) of ENKTL, and 13/48 (27.09%) of ANKL. Most mutations represented monoallelic and missense. Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations (P=0.0284, P=0.0137). Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV+T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.
Highlights
We collected a total of 177 Epstein-Barr virus (EBV)+T/nature killer (NK)-LPD patients including CAEBV-T/NK (n=50), EBV-associated hemophagocytic lymphohistiocytosis (EBV+HLH) (n=51), extranodal NK/T-cell lymphoma of nasal type (ENKTL) (n=28), and aggressive NK-cell leukemia (ANKL) (n=48)
Gross deletion and frameshift deletions were more common in EBV+HLH and ANKL
The mutation patterns of EBV+T/NK-LPDs demonstrated in our study provided us a novel insight into such spectrum of diseases
Summary
1.1 Patients and Samples This study was approved by the institutional review board of Tongji Hospital. Genomic DNA of peripheral blood samples and matched exfoliated cells of oral mucosa was extracted with QIAamp® DNA Blood Mini kit (Qiagen, Germany) according to the manufacturer’s instructions. Prognostic data were available in 50 EBV+HLH patients and 33 CAEBV-T/ NK. All these patients did not receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) before progression into accelerated phase. The variants detected from the patients were included if: (1) variants with allele frequency less than 0.01 according to the gnomAD; (2) confirmed as germline mutations by matched exfoliated cells of oral mucosa using Sanger sequencing . Progression-free survival (PFS) time of CAEBV-T/NK was defined as the time from the onset to the start of accelerated phase (progression into EBV+HLH, overt malignancies, or severe complications). A two-sided P-value
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