文章：

通过全基因组测序和靶向扩增子测序对EB病毒相关弥漫性大B细胞淋巴瘤发病机制的基因组学见解

Genomic insights into the pathogenesis of Epstein–Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing

原文发布日期：2021-05-26

DOI: 10.1038/s41408-021-00493-5

类型: Article

开放获取: 是

英文摘要：

Epstein–Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies.
 

摘要翻译： 

爱泼斯坦-巴尔病毒（EBV）相关的弥漫性大B细胞淋巴瘤，非特指型（DLBCL NOS），在现行世界卫生组织（WHO）分类中构成一个独特的临床病理实体。然而，其基因组特征仍鲜有描述。在此，我们结合了47例EBV阳性DLBCL（NOS）病例的全基因组测序（WGS）、靶向扩增子测序（tNGS）和荧光原位杂交（FISH），以描绘这种罕见疾病的基因组景观。整合的WGS和tNGS分析清楚地将这种肿瘤类型与EBV阴性DLBCL区分开来，原因是ARID1A（45%）、KMT2A/KMT2D（32%/30%）、ANKRD11（32%）或NOTCH2（32%）的频繁突变。WGS揭示了结构异常，包括6q缺失（5/8患者），随后通过FISH验证（14/32病例）。在先前报告的基础上，我们发现了CCR6（15%）、DAPK1（15%）、TNFRSF21（13%）、CCR7（11%）和YY1（6%）的反复改变。最后，通过顺序基因集富集和网络传播对突变景观进行功能注释，预测了对核因子κB（NFκB）通路（CSNK2A2、CARD10）、IL6/JAK/STAT（SOCS1/3、STAT3）和WNT信号传导（FRAT1、SFRP5）的影响，以及免疫过程（如干扰素反应）中的异常。这是对EBV阳性DLBCL（NOS）肿瘤的首次全面描述，证实了其病理生物学独立性的证据，并有助于对侵袭性淋巴瘤的分子分类进行分层，以期为未来治疗策略提供依据。

原文链接：

Genomic insights into the pathogenesis of Epstein–Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing