Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Clin Cancer Res. 2013 Jun 1;19(11):2893-904. doi: 10.1158/1078-0432.CCR-13-0138. Epub 2013 Apr 25.
The identification of gene mutations and structural genomic aberrations that are critically involved in chronic lymphocytic leukemia (CLL) pathogenesis is still evolving. One may postulate that genomic driver lesions with effects on CLL cell proliferation, apoptosis thresholds, or chemotherapy resistance should increase in frequency over time when measured sequentially in a large CLL cohort.
We sequentially sampled a large well-characterized CLL cohort at a mean of 4 years between samplings and measured acquired copy number aberrations (aCNA) and LOH using single-nucleotide polymorphism (SNP) 6.0 array profiling and the mutational state of TP53, NOTCH1, and SF3B1 using Sanger sequencing. The paired analysis included 156 patients, of whom 114 remained untreated and 42 received intercurrent therapies, predominantly potent chemoimmunotherapy, during the sampling interval.
We identify a strong effect of intercurrent therapies on the frequency of acquisition of aCNAs in CLL. Importantly, the spectrum of acquired genomic changes was largely similar in patients who did or did not receive intercurrent therapies; therefore, various genomic changes that become part of the dominant clones are often already present in CLL cell populations before therapy. Furthermore, we provide evidence that therapy of CLL with preexisting TP53 mutations results in outgrowth of genomically very complex clones, which dominate at relapse.
Using complementary technologies directed at the detection of genomic events that are present in substantial proportions of the clinically relevant CLL disease bulk, we capture aspects of genomic evolution in CLL over time, including increases in the frequency of genomic complexity, specific recurrent aCNAs, and TP53 mutations.
慢性淋巴细胞白血病（CLL）发病机制中关键涉及的基因突变和结构基因组异常的鉴定仍在不断发展。人们可以推测，在一个大的 CLL 队列中，随着时间的推移，当连续测量时，对 CLL 细胞增殖、凋亡阈值或化疗耐药性有影响的基因组驱动病变的频率应该会增加。
我们在平均 4 年的时间内对一个大型的、特征良好的 CLL 队列进行了连续采样，并使用单核苷酸多态性（SNP）6.0 阵列分析和 Sanger 测序测量获得的拷贝数异常（aCNA）和 LOH，以及 TP53、NOTCH1 和 SF3B1 的突变状态。配对分析包括 156 名患者，其中 114 名患者未接受治疗，42 名患者在采样间隔期间接受了当前的治疗，主要是强力化疗免疫治疗。
我们发现当前的治疗对 CLL 获得 aCNA 的频率有很强的影响。重要的是，在接受或未接受当前治疗的患者中，获得的基因组变化谱在很大程度上是相似的；因此，在治疗前，各种成为优势克隆一部分的基因组变化通常已经存在于 CLL 细胞群体中。此外，我们提供的证据表明，用具有预先存在的 TP53 突变的 CLL 进行治疗会导致具有非常复杂基因组的克隆的生长，这些克隆在复发时占主导地位。
使用互补技术检测临床上相关的 CLL 疾病中存在的大量基因组事件，我们可以捕捉到 CLL 中随时间推移的基因组进化方面的情况，包括基因组复杂性、特定的反复发生的 aCNA 和 TP53 突变频率的增加。
