Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Nat Med. 2018 May;24(5):679-690. doi: 10.1038/s41591-018-0016-8. Epub 2018 Apr 30.
Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.
弥漫性大 B 细胞淋巴瘤（DLBCL）是成人中最常见的淋巴恶性肿瘤，是一种临床上和遗传上具有异质性的疾病，进一步分为转录定义的激活 B 细胞（ABC）和生发中心 B 细胞（GCB）亚型。我们对 304 例原发性 DLBCL 进行了全面的遗传分析，确定了低频改变、捕获的反复突变、体细胞拷贝数改变和结构变异，并在有可用结局数据的患者中定义了协调的特征。我们使用共识聚类整合了这些遗传驱动因素，确定了五个稳健的 DLBCL 亚组，包括以前未被识别的滤泡外/边缘区起源的低风险 ABC-DLBCL 组；两个具有不同结局和可靶向改变的不同 GCB-DLBCL 亚组；以及一个 ABC/GCB 不依赖的组，其 TP53 双等位基因失活、CDKN2A 缺失和相关基因组不稳定性。新描述的亚组的遗传特征、其突变特征以及鉴定出的改变的时间顺序为 DLBCL 的发病机制提供了新的见解。协调的遗传特征也可预测独立于临床国际预后指数的结局，并提示新的联合治疗策略。更广泛地说，我们的结果为可操作的 DLBCL 分类提供了路线图。
