Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?
Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?
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DOI：
10.1101/mcs.a001719
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发表时间：
2017-05
影响因子：
1.8
通讯作者：
Schatz JH
中科院分区：
文献类型：
--
作者：
Amin AD;Peters TL;Li L;Rajan SS;Choudhari R;Puvvada SD;Schatz JH
基因表达谱和下一代测序将弥漫性大b细胞淋巴瘤（DLBCL）定义为一种异质性亚实体，这是最常见的淋巴瘤诊断。然而，尽管不断有数据揭示不同的致病机制，五药化学免疫治疗联合R-CHOP仍然是一线标准治疗。自从抗cd20单克隆抗体美罗华（rituximab）被添加到CHOP骨架中以来，这种情况在15年里没有改变，该抗体于20世纪70年代首次投入使用。至少三分之一的患者不能通过R-CHOP治疗治愈，90%的复发或难治性DLBCL是致命的。靶向小分子抑制剂针对不同亚组DLBCL中激活的不同分子途径，迄今为止在临床中的应用还很差，这证明了对R-CHOP和其他长期建立的化疗驱动组合的持续依赖。然而，尽管最近出现了一些挫折，但新药和改进的实时生物标志物识别显示出最终改变这种状况的潜力。在这里，我们回顾了通过大规模基因组学鉴定的DLBCL的已建立的和假定的分子驱动因素，强调了在区分驱动因素和乘客时必须注意的事项，这受到激活诱导的胞苷脱氨酶的混杂性的影响。此外，我们还讨论了为什么尽管有如此多的基因组数据可用，但很难对这种综合性疾病进行个性化治疗，以及可能采取的一些措施来加速这一进程。
Gene-expression profiling and next-generation sequencing have defined diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis, as a heterogeneous group of subentities. Despite ongoing explosions of data illuminating disparate pathogenic mechanisms, however, the five-drug chemoimmunotherapy combination R-CHOP remains the frontline standard treatment. This has not changed in 15 years, since the anti-CD20 monoclonal antibody rituximab was added to the CHOP backbone, which first entered use in the 1970s. At least a third of patients are not cured by R-CHOP, and relapsed or refractory DLBCL is fatal in ∼90%. Targeted small-molecule inhibitors against distinct molecular pathways activated in different subgroups of DLBCL have so far translated poorly into the clinic, justifying the ongoing reliance on R-CHOP and other long-established chemotherapy-driven combinations. New drugs and improved identification of biomarkers in real time, however, show potential to change the situation eventually, despite some recent setbacks. Here, we review established and putative molecular drivers of DLBCL identified through large-scale genomics, highlighting among other things the care that must be taken when differentiating drivers from passengers, which is influenced by the promiscuity of activation-induced cytidine deaminase. Furthermore, we discuss why, despite having so much genomic data available, it has been difficult to move toward personalized medicine for this umbrella disorder and some steps that may be taken to hasten the process.