Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. Here, we performed comprehensive genetic analysis of 177 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNAs), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X (chrX) losses were the most common arm-level CNAs in females (~40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chrX losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines demonstrated that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, non-negative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognosis irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL.

中文翻译：

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全面的基因分析揭示结外 NK/T 细胞淋巴瘤 X 染色体上驱动基因的频繁改变

结外 NK/T 细胞淋巴瘤 (ENKTCL) 是一种与 Epstein-Barr 病毒 (EBV) 相关的肿瘤，以男性为主，预后不良。更好地了解 ENKTCL 中的基因改变及其功能作用有助于改善患者分层和治疗。在这里，我们对 177 个 ENKTCL 病例进行了全面的遗传分析，以描绘突变、拷贝数改变 (CNA) 和结构变异的情况，识别出 34 个驱动基因，其中包括 6 个以前未被识别的基因，即 HLA-B、HLA-C、ROBO1、 CD58、POT1 和 MAP2K1。其中，CD274 (24%) 改变最频繁，其次是 TP53 (20%)、CDKN2A (19%)、ARID1A (15%)、HLA-A (15%)、BCOR (14%) 和 MSN (14%)。 X 染色体 (chrX) 丢失是女性中最常见的臂级 CNA（约 40%），四个 X 连锁驱动基因（MSN、BCOR、DDX3X 和 KDM6A）的改变在携带 chrX 的男性和女性中更为常见损失。在 X 连锁驱动因素中，MSN 是最常发生改变的，并且使用免疫组织化学分析，大约三分之一的病例中其表达丢失。人类细胞系的功能研究表明，MSN 破坏可促进细胞增殖和 NF-κB 激活。此外，MSN 失活增加了体外和体内对 NF-κB 抑制的敏感性。此外，在 EBV 基因组复制起点处观察到反复缺失（6%）。最后，通过整合 34 个驱动因素和 19 个重要的臂级 CNA，非负矩阵分解和共识聚类确定了两个具有不同遗传特征和预后的分子组，无论临床预后因素如何。总之，这些发现可能有助于改善 ENKTCL 的诊断和治疗策略。