Inherited Genetic Susceptibility to Nonimmunosuppressed Epstein-Barr Virus-associated T/NK-cell Lymphoproliferative Diseases in Chinese Patients

Epstein-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(CAEBVT/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 UNCI 3D,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.