Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade
Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade
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DOI：
10.1182/blood.2019002067
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发表时间：
2019-12-26
期刊：
影响因子：
20.3
通讯作者：
Shipp, Margaret A.
中科院分区：
文献类型：
--
作者：
Chapuy, Bjoern;Stewart, Chip;Shipp, Margaret A.
原发性纵隔大b细胞淋巴瘤（PMBLs）是侵袭性肿瘤，典型表现为年轻女性纵隔大肿块。PMBLs与经典霍奇金淋巴瘤（cHL）具有相同的临床、转录和分子特征，包括核因子KB （NF-kappa B）的组成性激活、JAK/STAT信号传导和程序性细胞死亡蛋白1 （PD-1）介导的免疫逃避。PD-1阻断治疗复发/难治性PMBLs的有效性最近获得了美国食品和药物管理局的批准，并强调了表征该疾病中可靶向遗传脆弱性的重要性。在这里，我们报告了对37例新诊断的PMBLs队列中复发性遗传改变的综合分析-体细胞突变，体细胞拷贝数改变和结构变异。我们发现每个PMBL中有9个遗传驱动因素，包括已知和新发现的JAK/STAT和NF-KB信号通路的成分，以及限制主要组织相容性复合体I类表达的频繁B2M改变，如cHL。PMBL在ZNF217和一个额外的表观遗传修饰因子EZH2中也表现出频繁的、新发现的驱动突变。这些改变中的大多数是克隆的，这支持了它们作为早期驱动因素的作用。在PMBL中，我们发现了几个以前未表征的可能增加PD-1阻断敏感性的分子特征，包括高肿瘤突变负担、微卫星不稳定性和载脂蛋白蛋白B mRNA编辑催化多肽样（APOBEC）突变特征。PMBL和cHL之间的共同遗传特征为分析PD-1阻断在这些相关淋巴细胞恶性肿瘤中的作用机制提供了框架。
Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor KB (NF-kappa B), JAK/STAT signaling, and programmed cell death protein 1 (PD-1)-mediated immune evasion. The demonstrated efficacy of PD-1 blockade in relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration and underscored the importance of characterizing targetable genetic vulnerabilities in this disease. Here, we report a comprehensive analysis of recurrent genetic alterations-somatic mutations, somatic copy number alterations, and structural variants-in a cohort of 37 newly diagnosed PMBLs. We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-KB signaling pathways and frequent B2M alterations that limit major histocompatibility complex class I expression, as in cHL. PMBL also exhibited frequent, newly identified driver mutations in ZNF217 and an additional epigenetic modifier, EZH2. The majority of these alterations were clonal, which supports their role as early drivers. In PMBL, we identified several previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high tumor mutational burden, microsatellite instability, and an apolipo protein B mRNA editing catalytic polypeptide-like (APOBEC) mutational signature. The shared genetic features between PMBL and cHL provide a framework for analyzing the mechanism of action of PD-1 blockade in these related lymphoid malignancies.