Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Harvard Medical School, Boston, MA.
Blood Adv. 2019 Dec 10;3(23):4065-4080. doi: 10.1182/bloodadvances.2019001012.
Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry-sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus-positive (EBV+) tumors. We identified significantly mutated cancer candidate genes (CCGs) as well as somatic copy number alterations and structural variations and characterized their contribution to disease-defining immune evasion mechanisms and nuclear factor κB (NF-κB), JAK/STAT, and PI3K signaling pathways. EBV- cHLs had a higher prevalence of genetic alterations in the NF-κB and major histocompatibility complex class I antigen presentation pathways. In this young cHL cohort (median age, 26 years), we identified a predominant mutational signature of spontaneous deamination of cytosine- phosphate-guanines ("Aging"), in addition to apolipoprotein B mRNA editing catalytic polypeptide-like, activation-induced cytidine deaminase, and microsatellite instability (MSI)-associated hypermutation. In particular, the mutational burden in EBV- cHLs was among the highest reported, similar to that of carcinogen-induced tumors. Together, the overall high mutational burden, MSI-associated hypermutation, and newly identified genetic alterations represent additional potential bases for the efficacy of PD-1 blockade in cHL. Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases.
经典型霍奇金淋巴瘤（cHL）由罕见的恶性霍奇金里德-斯特恩伯格（HRS）细胞和广泛但无效的炎症/免疫细胞浸润组成。HRS 细胞表现出几乎普遍的染色体 9p/9p24.1 的体细胞拷贝数增加，从而增加程序性细胞死亡蛋白 1（PD-1）配体的表达。为了确定对 PD-1 阻断的反应和耐药的遗传机制，并确定互补的治疗靶点，我们对 23 例新诊断的 cHL 切除活检中流式细胞术分选的 HRS 细胞进行了全外显子测序，包括 8 例 EBV 阳性（EBV+）肿瘤。我们鉴定了显著突变的癌症候选基因（CCGs）以及体细胞拷贝数改变和结构变异，并对其在疾病定义性免疫逃逸机制和核因子 κB（NF-κB）、JAK/STAT 和 PI3K 信号通路中的作用进行了特征描述。EBV-cHL 中 NF-κB 和主要组织相容性复合体 I 抗原呈递途径的遗传改变更为常见。在这个年轻的 cHL 队列（中位年龄 26 岁）中，我们除了鉴定出脱氨酶诱导的胞嘧啶-磷酸-鸟嘌呤自发脱氨（“衰老”）的主要突变特征外，还鉴定出载脂蛋白 B mRNA 编辑催化多肽样、激活诱导的胞嘧啶脱氨酶和微卫星不稳定性（MSI）相关的超突变。特别是，EBV-cHL 中的突变负担是报告的最高之一，与致癌物诱导的肿瘤相似。总的来说，高突变负担、MSI 相关的超突变以及新发现的遗传改变代表了 PD-1 阻断在 cHL 中的疗效的额外潜在基础。值得注意的是，反复出现的 cHL 改变，包括 B2M、TNFAIP3、STAT6、GNA13 和 XPO1 突变以及 2p/2p15、6p21.32、6q23.3 和 9p/9p24.1 拷贝数改变，也在 >20%的原发性纵隔 B 细胞淋巴瘤中被发现，突出了这些疾病中共同的发病机制。
