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

Summary 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.