Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas
Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas
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DOI：
10.1038/s41375-019-0380-5
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发表时间：
2019-07-01
期刊：
影响因子：
11.4
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
--
作者：
Kataoka, Keisuke;Miyoshi, Hiroaki;Ogawa, Seishi
病毒感染诱导有效的细胞免疫和激活的细胞内信号传导，这可能决定参与病毒相关癌症（包括EB病毒（EBV）阳性淋巴瘤）的免疫逃逸和克隆选择的驱动事件。在这里，我们使用高通量测序技术，对来自不同淋巴瘤亚型的384例样本中涉及PD-L1/PD-L2的体细胞畸变进行了彻底的调查，特别是关注病毒相关淋巴瘤。在EBV阳性淋巴瘤中观察到涉及PD-L1/PD-L2的遗传畸变的高频率[33/148例（22%）]，包括淋巴结NK/T细胞淋巴瘤（ENKTL，23%）、侵袭性NK细胞白血病（57%）、系统性EBV阳性T细胞淋巴增生性疾病（17%）以及EBV阳性弥漫性大B细胞淋巴瘤（DLBCL，19%）和外周T细胞淋巴瘤-未另行说明（15%）。这些改变主要引起3 '-非翻译区的截短，代表了ENKTL中最普遍的体细胞病变。相比之下，无论组织学类型如何，EBV阴性淋巴瘤的频率都要低得多[12/236例（5%）]。除了PD-L1/PD-L2改变外，EBV阳性DLBCL表现出与EBV阴性DLBCL不同的遗传特征，其特征在于频繁的TET 2和DNMT 3A突变以及CD 79 B、MYD 88、CDKN 2A和FAS改变的缺乏。我们的研究结果说明了EBV相关淋巴瘤的独特遗传特征，也表明了检测PD-L1/PD-L2相关病变的潜在作用，这些淋巴瘤可以通过免疫检查点阻断有效靶向。
Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3'-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.