Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Haematologica. 2011 Aug;96(8):1161-9. doi: 10.3324/haematol.2010.039768. Epub 2011 May 5.
High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution.
We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years.
At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV.
Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
高分辨率基因组微阵列能够同时检测拷贝数异常，如慢性淋巴细胞白血病中已知的反复出现的异常[del(11q)、del(13q)、del(17p)和三体 12]，以及拷贝数中性杂合性缺失。此外，比较连续患者样本的基因组图谱可以检测到克隆进化。
我们使用 250K 单核苷酸多态性阵列对来自基于人群队列的 369 例新诊断的慢性淋巴细胞白血病患者的样本进行了筛选。在 5-9 年后获得的 59 个随访样本中评估了克隆进化。
在诊断时，90%的患者存在拷贝数异常；70%的患者携带已知的反复改变，包括 del(13q)（55%）、三体 12（10.5%）、del(11q)（10%）和 del(17p)（4%）。在染色体 2（1.9%）、4（1.4%）、8（1.6%）和 14（1.6%）上还检测到其他反复出现的异常。13 例患者（3.5%）表现出 13q 上的复发性拷贝数中性杂合性缺失，其中 11 例伴有同源性 del(13q)。基因组复杂性和大的 13q 缺失与预后不良相关，而前者与预后不良的异常相关。在随访研究中，24 例 IGHV 未突变的患者中有 8 例（33%）发生了克隆进化，25 例 IGHV 突变且接受治疗的患者中有 4 例（16%）发生了克隆进化。相比之下，未接受治疗但 IGHV 突变的 10 例患者没有获得额外的异常。在所有获得改变的患者中，最常见的次要事件 del(13q)在 6/12（50%）例患者中被检出。有趣的是，染色体 6q、8p、9p 和 10q 上的异常仅在 IGHV 未突变的患者中出现。
全基因组筛查显示新诊断的慢性淋巴细胞白血病中存在高频的基因组异常。克隆进化与其他侵袭性疾病的标志物相关，通常包括已知的反复出现的异常。
