Extra-nodal NK/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive Epstein-Barr virus associated lymphoma, typically presenting in the nasal and paranasal areas. We assembled a large series of ENKTCL (n = 209) for comprehensive genomic analysis and correlative clinical study. The International Lymphoma Prognostic Index (IPI), site of disease, stage, lymphadenopathy, and hepatomegaly were associated with overall survival. Genetic analysis revealed frequent oncogenic activation of the JAK/STAT3 pathway and alterations in tumor suppressor genes (TSGs) and genes associated with epigenomic regulation. Integrated genomic analysis including recurrent mutations and genomic copy number alterations using consensus clustering identified seven distinct genetic clusters that were associated with different clinical outcomes, thus constituting previously unrecognized risk groups. The genetic profiles of ENTKCLs from Asian and Hispanic ethnic groups showed striking similarity, indicating shared pathogenetic mechanism and tumor evolution. Interestingly, we discovered a novel functional cooperation between activating STAT3 mutations and loss of the TSG, PRDM1, in promoting NK-cell growth and survival. This study provides a genetic roadmap for further analysis and facilitates investigation of actionable therapeutic opportunities in this aggressive lymphoma.

鼻型结外 NK/T 细胞淋巴瘤 (ENKTCL) 是一种高度侵袭性 Epstein-Barr 病毒相关淋巴瘤，通常出现在鼻和鼻旁区域。我们收集了一系列 ENKTCL（ n = 209）用于全面的基因组分析和相关临床研究。国际淋巴瘤预后指数（IPI）、疾病部位、分期、淋巴结肿大和肝肿大与总生存期相关。遗传分析揭示了 JAK/STAT3 通路的频繁致癌激活以及肿瘤抑制基因 (TSG) 和与表观基因组调控相关的基因的改变。综合基因组分析（包括使用共识聚类的反复突变和基因组拷贝数改变）确定了与不同临床结果相关的七个不同的遗传簇，从而构成了以前未被识别的风险组。来自亚洲和西班牙裔群体的 ENTKCL 的基因谱显示出惊人的相似性，表明共同的发病机制和肿瘤进化。有趣的是，我们发现激活STAT3突变和 TSG、 PRDM1缺失之间存在一种新的功能协同作用，可促进 NK 细胞生长和存活。这项研究为进一步分析提供了遗传路线图，并有助于研究这种侵袭性淋巴瘤的可行治疗机会。