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EBV 相关弥漫性大 B 细胞淋巴瘤的分子特征分析。

Molecular profiling of EBV associated diffuse large B-cell lymphoma.

机构信息

Department of Medicine A, Department of Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany.

Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany.

出版信息

Leukemia. 2023 Mar;37(3):670-679. doi: 10.1038/s41375-022-01804-w. Epub 2023 Jan 5.

DOI:10.1038/s41375-022-01804-w
PMID:36604606
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9991915/
Abstract

Epstein-Barr virus (EBV) associated diffuse large B-cell lymphoma (DLBCL) represents a rare aggressive B-cell lymphoma subtype characterized by an adverse clinical outcome. EBV infection of lymphoma cells has been associated with different lymphoma subtypes while the precise role of EBV in lymphomagenesis and specific molecular characteristics of these lymphomas remain elusive. To further unravel the biology of EBV associated DLBCL, we present a comprehensive molecular analysis of overall 60 primary EBV positive (EBV+) DLBCLs using targeted sequencing of cancer candidate genes (CCGs) and genome-wide determination of recurrent somatic copy number alterations (SCNAs) in 46 cases, respectively. Applying the LymphGen classifier 2.0, we found that less than 20% of primary EBV + DLBCLs correspond to one of the established molecular DLBCL subtypes underscoring the unique biology of this entity. We have identified recurrent mutations activating the oncogenic JAK-STAT and NOTCH pathways as well as frequent amplifications of 9p24.1 contributing to immune escape by PD-L1 overexpression. Our findings enable further functional preclinical and clinical studies exploring the therapeutic potential of targeting these aberrations in patients with EBV + DLBCL to improve outcome.

摘要

EBV 相关弥漫性大 B 细胞淋巴瘤（DLBCL）是一种罕见的侵袭性 B 细胞淋巴瘤亚型，其临床结局较差。EBV 感染淋巴瘤细胞与不同的淋巴瘤亚型有关，而 EBV 在淋巴瘤发生中的确切作用和这些淋巴瘤的特定分子特征仍不清楚。为了进一步阐明 EBV 相关 DLBCL 的生物学特性，我们对 60 例原发性 EBV 阳性（EBV+）DLBCL 进行了全面的分子分析，分别对 46 例进行了癌症候选基因（CCGs）的靶向测序和全基因组复发性体细胞拷贝数改变（SCNAs）的测定。应用 LymphGen 分类器 2.0，我们发现不到 20%的原发性 EBV+DLBCL 符合已建立的分子 DLBCL 亚型之一，这突出了该实体的独特生物学特性。我们已经鉴定出激活致癌 JAK-STAT 和 NOTCH 通路的反复突变，以及 9p24.1 的频繁扩增，导致 PD-L1 过表达的免疫逃逸。我们的研究结果使我们能够进一步进行功能临床前和临床研究，探索针对 EBV+DLBCL 患者这些异常的治疗潜力，以改善预后。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/4c7fd5aaa7f1/41375_2022_1804_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/ed1d962fbae9/41375_2022_1804_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/2790bd1a936d/41375_2022_1804_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/5d7e629813ca/41375_2022_1804_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/d1315e1fb604/41375_2022_1804_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/4c7fd5aaa7f1/41375_2022_1804_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/ed1d962fbae9/41375_2022_1804_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/2790bd1a936d/41375_2022_1804_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/5d7e629813ca/41375_2022_1804_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/d1315e1fb604/41375_2022_1804_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a24/9991915/4c7fd5aaa7f1/41375_2022_1804_Fig5_HTML.jpg

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