Department of Pathology, West China Hospital of Sichuan University , Chengdu , China.
Department of Dermatology and Venerology, West China Hospital of Sichuan University , Chengdu , China.
Cancer Biol Ther. 2019;20(10):1319-1327. doi: 10.1080/15384047.2019.1638670. Epub 2019 Jul 16.
Limited studies are available on the molecular pathogenesis of Epstein-Barr virus (EBV)-associated T or natural killer (NK) cell lymphoproliferative disorders (EBV+T/NK-LPD). In this retrospective study, we aim to elucidate the mutation profile of EBV+T/NK-LPD using capture-based targeted sequencing with a panel consisting of 64 lymphoma-related genes to identify driver genes associated with the development of EBV+T/NK-LPD. Targeted sequencing of 169 EBV+T/NK-LPD cases was performed using a panel of 64 lymphoma-related genes. Of the 169 EBV+T/NK-LPD cases, 123 had extra-nodal NK/T-cell lymphoma (ENKTL), 12 had aggressive NK-cell leukemia (ANKL) and 34 had EBV+ T-cell lymphoma of childhood (EBV+TL). The mutation profile revealed that all three subtypes of EBV+T/NK-LPDs had high mutation rates in and . Target sequencing revealed that ENKTL, ANKL and EBV+TL were molecularly distinct, the mutation in nasal-ENKTL and extra-nasal-ENKTL are also different. Survival analysis revealed that ENKTL patients with gene mutations or loss of protein expression in either KMT2D or TET2 were significantly correlated with shorter overall survival. And although the EBV+TL and ANKL groups were too small to confirm survival disadvantage, the adverse prognosis trends of KMT2D or TET2 were showed in these two groups. We conclude that EBV+T/NK lymphoproliferative disorders have very distinct molecular profiles. Our findings also suggest the likely involvement of KMT2D and TET2 in the development of ENKTL, and possibly EBV+T/NK-LPDs in general.
关于 Epstein-Barr 病毒（EBV）相关 T 或自然杀伤（NK）细胞淋巴增生性疾病（EBV+T/NK-LPD）的分子发病机制的研究有限。在这项回顾性研究中，我们旨在使用包含 64 个淋巴瘤相关基因的基于捕获的靶向测序阐明 EBV+T/NK-LPD 的突变谱，以鉴定与 EBV+T/NK-LPD 发展相关的驱动基因。使用包含 64 个淋巴瘤相关基因的panel 对 169 例 EBV+T/NK-LPD 病例进行靶向测序。在 169 例 EBV+T/NK-LPD 病例中，123 例为结外 NK/T 细胞淋巴瘤（ENKTL），12 例为侵袭性 NK 细胞白血病（ANKL），34 例为儿童 EBV+T 细胞淋巴瘤（EBV+TL）。突变谱显示，所有三种亚型的 EBV+T/NK-LPDs 在 和 中均具有高突变率。靶向测序显示，ENKTL、ANKL 和 EBV+TL 在分子上是不同的，鼻型 ENKTL 和鼻外型 ENKTL 的突变也不同。生存分析显示，在 KMT2D 或 TET2 中发生基因突变或蛋白表达缺失的 ENKTL 患者与总生存期显著缩短相关。尽管 EBV+TL 和 ANKL 组太小，无法确认生存劣势，但在这两组中也显示出 KMT2D 或 TET2 的不良预后趋势。我们得出结论，EBV+T/NK 淋巴增生性疾病具有非常不同的分子谱。我们的研究结果还表明，KMT2D 和 TET2 可能参与了 ENKTL 的发生，并且可能在一般情况下也参与了 EBV+T/NK-LPDs 的发生。
