Amin Amit Dipak, Peters Tara L, Li Lingxiao, Rajan Soumya Sundara, Choudhari Ramesh, Puvvada Soham D, Schatz Jonathan H
Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Cold Spring Harb Mol Case Stud. 2017 May;3(3):a001719. doi: 10.1101/mcs.a001719.
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.
基因表达谱分析和下一代测序已将弥漫性大B细胞淋巴瘤（DLBCL，最常见的淋巴瘤诊断类型）定义为一组异质性的亚实体。然而，尽管不断涌现的数据揭示了不同的致病机制，但由五种药物组成的化疗免疫疗法组合R-CHOP仍然是一线标准治疗方案。自20世纪70年代首次使用的CHOP方案加入抗CD20单克隆抗体利妥昔单抗以来，15年过去了，这一情况并未改变。至少三分之一的患者无法通过R-CHOP治愈，复发或难治性DLBCL的致死率约为90%。针对DLBCL不同亚组中激活的不同分子途径的靶向小分子抑制剂，到目前为止在临床上的转化效果不佳，这使得人们仍依赖R-CHOP和其他长期使用的以化疗为主的联合治疗方案。然而，尽管最近遇到了一些挫折，但新药和实时改进的生物标志物识别方法最终显示出改变这种状况的潜力。在这里，我们回顾通过大规模基因组学确定的DLBCL已确定的和推测的分子驱动因素，特别强调在区分驱动因素和乘客因素时必须谨慎，这受到激活诱导的胞苷脱氨酶的多效性影响。此外，我们讨论了为什么尽管有如此多的基因组数据可用，但针对这种综合性疾病转向个性化医疗却很困难，以及可能采取哪些步骤来加速这一进程。
