INSERM UMR 892, CNRS UMR 6299, Université de Nantes, Nantes, France.
Leukemia. 2013 Feb;27(2):473-81. doi: 10.1038/leu.2012.226. Epub 2012 Aug 9.
Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations' control to eradicate all myeloma subclones in order to obtain long-term remission.
最近的研究为各种癌症类型的亚克隆遗传变异提供了直接证据。然而，对于多发性骨髓瘤 (MM) 中根据治疗和随后的复发出现的亚克隆进化过程，人们知之甚少。这项研究在一个 24 名 MM 患者的队列中进行，这些患者接受了常规化疗或蛋白酶体抑制剂硼替佐米治疗。由于 MM 是一种与大量染色体异常相关的高度异质性疾病，因此研究人员检查了一组似乎反映进展的次要遗传事件，包括 1q21 增益、NF-κB 激活突变、RB1 和 TP53 缺失。通过使用高分辨率单核苷酸多态性阵列，鉴定出具有非线性复杂进化史的亚克隆。在治疗期间，三分之一的 MM 患者中发现了这种遗传病变谱的重新排序，这可能反映了具有不同遗传特征的亚克隆的选择，这些亚克隆最初并不与优势群体竞争，但在化疗后存活、茁壮成长并获得新的异常。此外，在复发时出现的次要亚克隆的出现似乎与硼替佐米治疗显著相关。这些数据支持这样一种观点，即 MM 未来临床试验的新策略应该将靶向治疗和亚群控制相结合，以根除所有骨髓瘤亚克隆，从而获得长期缓解。
