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.

中文翻译：

---

弥漫性大B细胞淋巴瘤的分子亚型与独特的致病机制和结果相关。

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，是一种临床和遗传异质性疾病，可进一步分为转录定义的活化B细胞（ABC）和生发中心B细胞（GCB）亚型。我们对304例原发性DLBCLs进行了全面的遗传分析，发现了低频变化，捕获的复发突变，体细胞拷贝数变化和结构变异，并定义了具有可用结果数据的患者的坐标特征。我们使用共识聚类方法整合了这些遗传驱动因素，并确定了五个健壮的DLBCL亚集，包括先前未被认识到的来自毛囊外/边缘区的低风险ABC-DLBCL组。GCB-DLBCL的两个截然不同的子集，具有不同的结果和可针对性的变更；以及一个不依赖ABC / GCB的组，该组具有TP53的双等位基因失活，CDKN2A缺失以及相关的基因组不稳定性。新近表征的子集的遗传特征，它们的突变特征以及已鉴定出的变化的时间顺序，为DLBCL发病机理提供了新的见解。协调的遗传标记还可以独立于临床国际预后指数预测预后，并提出新的联合治疗策略。更广泛地说，我们的结果为可行的DLBCL分类提供了路线图。协调的遗传标记还可以独立于临床国际预后指数预测预后，并提出新的联合治疗策略。更广泛地说，我们的结果为可行的DLBCL分类提供了路线图。协调的遗传标记还可以独立于临床国际预后指数预测预后，并提出新的联合治疗策略。更广泛地说，我们的结果为可行的DLBCL分类提供了路线图。