The mutational landscape of Hodgkin lymphoma cell lines determined by whole exome sequencing

Hodgkin lymphoma (HL) is characterized by a minority of B cell derived tumor cells, named Hodgkin Reed-Sternberg (HRS) cells in classical (c)HL and lymphocyte predominant (LP) cells in nodular lymphocyte predominant (NLP) HL. HRS cells lack expression of the B cell receptor in most cases and rely on activation of multiple pathways to escape from apoptosis in the germinal center reaction.1 Constitutive activation of the NF-?B pathway is achieved by activation of various signaling pathways, e.g. CD30, CD40-CD40L and Epstein Barr virus (EBV)-derived latent membrane protein 1 (LMP1). In addition, NF-?B activation is caused by diverse aberrations in multiple genes involved in the NF-?B pathway, such as amplifications of REL, gains of MAP3K14, mutations of TNFAIP3, NFKBIA and NFKBIE. A second pathway frequently altered in HRS cells is the JAK/STAT signaling pathway. Activation is caused by gains of JAK2 and inactivating mutations of SOCS1. In recent years, high-throughput sequencing technology has provided novel opportunities for the comprehensive identification of genetic aberrations involved in various types of cancer. To increase our understanding of the pathogenesis of HL, we performed whole exome sequencing (WES) in seven cell lines to identify commonly mutated genes in HL.

霍奇金淋巴瘤（HL）以少量B细胞来源的肿瘤细胞为特征，经典型（c）HL中的肿瘤细胞称为霍奇金-里-施（HRS）细胞，结节性淋巴细胞为主型（NLP）HL中的肿瘤细胞则为淋巴细胞为主型（LP）细胞。在大多数情况下，HRS细胞不表达B细胞受体，并依赖多条通路的激活以逃过生发中心反应中的细胞凋亡过程¹。核因子κB（NF-κB）通路的组成性激活可通过多种信号通路的激活实现，例如CD30、CD40-CD40L通路以及爱泼斯坦-巴尔病毒（EBV）编码的潜伏膜蛋白1（LMP1）。此外，NF-κB通路相关的多个基因发生多种畸变也可导致该通路激活，例如REL基因扩增、MAP3K14基因拷贝数增加、TNFAIP3、NFKBIA及NFKBIE基因突变。HRS细胞中另一个常发生异常改变的通路是JAK/STAT信号通路，其激活由JAK2基因拷贝数增加以及SOCS1基因失活突变所介导。近年来，高通量测序技术为全面鉴定各类癌症相关的遗传畸变提供了全新的契机。为加深我们对霍奇金淋巴瘤发病机制的理解，本研究对7株细胞系开展全外显子组测序（WES），以鉴定霍奇金淋巴瘤中常见的突变基因。