Meriranta Leo, Pasanen Annika, Alkodsi Amjad, Haukka Jari, Karjalainen-Lindsberg Marja-Liisa, Leppä Sirpa
Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Blood Adv. 2020 Aug 11;4(15):3742-3753. doi: 10.1182/bloodadvances.2020001727.
Concomitant deregulation of MYC and BCL2 comprises clinically significant, yet poorly characterized biological high-risk feature in diffuse large B-cell lymphoma (DLBCL). To interrogate these lymphomas, we analyzed translocations and protein expression of BCL2, BCL6, and MYC; correlated the findings with comprehensive mutational, transcriptomic, and clinical data in 181 patients with primary DLBCL; and validated the key findings in independent data sets. Structural variations of BCL2 were subtype-specific and specifically increased BCL2 expression. Molecular dissection of MYC deregulation revealed associations with other lymphoma drivers, including loss of TP53, and distinctive gene expression profiles. Double protein expression (DPE) arose from heterogeneous molecular backgrounds that exhibited subtype-dependent patterns. In the germinal center B-cell (GCB) DLBCL, concurrent alterations of MYC and BCL2 loci gave rise to the majority of DPE DLBCLs, whereas among the activated B-cell (ABC) DLBCLs, concurrent alterations were infrequent. Clinically, DPE DLBCL defined a prognostic entity, which was independent of the International Prognostic Index (IPI) and cell of origin, and together with the loss of TP53 had a synergistic dismal impact on survival. In the DPE DLBCL, the loss of TP53 was associated with a chemorefractory disease, whereas among the other DLBCLs, no correlation with survival was seen. Importantly, BCL6 translocations identified non-GCB lymphomas with favorable BN2/C1-like survival independent of IPI and concurrent DPE status. Taken together, our findings define molecular characteristics of the DPE in DLBCL, and recognize clinically feasible predictors of outcome. Given the emerging taxonomical significance of BCL2, BCL6, MYC, and TP53, our findings provide further depth and validation to the genomic classification of DLBCL.
MYC和BCL2的同时失调是弥漫性大B细胞淋巴瘤（DLBCL）中具有临床意义但特征不明的生物学高风险特征。为了研究这些淋巴瘤，我们分析了BCL2、BCL6和MYC的易位及蛋白表达；将这些结果与181例原发性DLBCL患者全面的突变、转录组和临床数据相关联；并在独立数据集中验证了关键发现。BCL2的结构变异具有亚型特异性，并特异性增加了BCL2的表达。对MYC失调的分子剖析揭示了其与其他淋巴瘤驱动因素的关联，包括TP53缺失，以及独特的基因表达谱。双蛋白表达（DPE）源于表现出亚型依赖性模式的异质分子背景。在生发中心B细胞（GCB）DLBCL中，MYC和BCL2基因座的同时改变导致了大多数DPE DLBCL，而在活化B细胞（ABC）DLBCL中，同时改变并不常见。临床上，DPE DLBCL定义了一个预后实体，它独立于国际预后指数（IPI）和细胞起源，并与TP53缺失一起对生存产生协同不良影响。在DPE DLBCL中，TP53缺失与化疗难治性疾病相关，而在其他DLBCL中，未观察到与生存相关联之处。重要的是，BCL6易位确定了具有独立于IPI和并发DPE状态而具有良好BN2/C1样生存的非GCB淋巴瘤类型。综上所述，我们的发现定义了DLBCL中DPE的分子特征，并识别出临床上可行且可预测预后结局的指标。鉴于BCL2、BCL6、MYC和TP53在分类学上的新意义，我们的发现为DLBCL的基因组分类提供了进一步的深度和验证。
