Germline defects of familial haemophagocytic lymphohistiocytosis—Related genes may represent a predisposing factor for mature T- and natural killer-cell lymphoma

Peripheral T-cell lymphoma (PTCL) is relatively prevalent in Asian populations. Previous studies suggest that germline mutations in familial haemophagocytic lymphohistiocytosis (FHL)-related genes may predispose individuals to lymphoproliferative disorders. To investigate the underlying molecular mechanisms, we analysed paired tumour and germline deoxyribonucleic acid from 74 patients with T- and natural killer-cell lymphomas. Germline variants in FHL-related genes (UNC13D, PRF1, STXBP2, STX11, SH2D1A and XIAP) were assessed by whole-exome sequencing, while somatic mutations were analysed by targeted sequencing. A total of 21 germline mutations in FHL-related genes were detected in 14 of 74 patients (18.9%), including mutations in UNC13D (N = 11), STXBP2 (N = 6), PRF1 (N = 3) and STX11 (N = 1). The most frequent mutation was UNC13D c.2588G>A (p.G863D), which was significantly enriched in PTCL patients compared to the general Chinese Han population (allele frequency: 4.7% vs. 0.7%, OR = 6.785, p = 0.002). In line with established PTCL mutation profiles, somatic mutations were frequently detected in TET2, RHOA, DNMT3A and IDH2. Patients with FHL-related germline mutations exhibited a trend towards better overall survival. In conclusion, germline mutations in FHL-related genes, particularly UNC13D, may contribute to PTCL susceptibility in Chinese patients and are associated with clonal somatic mutations.