Laboratorio de Mutagénesis, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
División Patología Molecular, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
Mutagenesis. 2019 Sep 20;34(3):245-252. doi: 10.1093/mutage/gez009.
Genomic instability is a hallmark of cancer, contributing to tumour development and transformation, being chromosome instability (CIN) the most common form in human cancer. Chronic lymphocytic leukaemia (CLL) is the most frequent adult leukaemia in the Western world. In this study, we have evaluated basal CIN in untreated patients with CLL by measuring chromosome aberrations (CAs) and micronucleus (MN) frequency and their association with different prognostic factors. Seventy-two patients and 21 normal controls were analysed. Cytogenetic and fluorescence in situ hybridisation (FISH) studies were performed. IGHV (immunoglobulin heavy chain variable region) mutational status was evaluated by reverse transcription polymerase chain reaction and sequencing. An increased number of CA in patients compared with controls (P = 0.0001) was observed. Cases with abnormal karyotypes showed increased CA rate than those with normal karyotypes (P = 0.0026), with a particularly highest frequency in cases with complex karyotypes. Among FISH risk groups, a significant low frequency of CA was found in patients with no FISH alterations compared to those with del13q14 and ≥2 FISH alterations (P = 0.0074). When mean CA value (6.7%) was considered, significant differences in the distribution of low and high CA frequency between cases with normal and abnormal karyotypes (P = 0.002) were observed. By MN analysis, higher frequency in patients compared to controls (P = 0.0001) was also found, as well as between cases with ≥2 FISH abnormalities and those with no FISH alterations (P = 0.026). Similarly, significant differences were observed when patients were divided according to mean MN frequency (2.2%; P ≤ 0.04). Interestingly, patients with high MN frequency had shorter time to first treatment than those with low frequency (P = 0.024). Cases with mutated and unmutated IGHV status showed increased CA and MN frequencies compared to controls (P ≤ 0.0007), but no differences between both groups were found. Our results support the strong interaction between CIN and genomic complexity as well as their influence on poor outcome in this pathology.
基因组不稳定性是癌症的一个标志，导致肿瘤的发生和转化，其中染色体不稳定性（CIN）是人类癌症中最常见的形式。慢性淋巴细胞白血病（CLL）是西方世界最常见的成人白血病。在这项研究中，我们通过测量染色体畸变（CAs）和微核（MN）的频率来评估未经治疗的 CLL 患者的基础 CIN，并将其与不同的预后因素相关联。分析了 72 例患者和 21 例正常对照。进行了细胞遗传学和荧光原位杂交（FISH）研究。通过逆转录聚合酶链反应和测序评估 IGHV（免疫球蛋白重链可变区）突变状态。与对照组相比，患者的 CA 数量增加（P = 0.0001）。核型异常的病例比核型正常的病例 CA 率更高（P = 0.0026），其中复杂核型的病例频率最高。在 FISH 风险组中，与无 FISH 改变的患者相比，del13q14 和≥2 个 FISH 改变的患者的 CA 频率明显较低（P = 0.0074）。当考虑平均 CA 值（6.7%）时，在核型正常和异常病例之间，低和高 CA 频率的分布存在显著差异（P = 0.002）。通过 MN 分析，与对照组相比，患者的频率也更高（P = 0.0001），并且在具有≥2 个 FISH 异常的病例与无 FISH 改变的病例之间也存在差异（P = 0.026）。同样，当根据平均 MN 频率（2.2%；P ≤ 0.04）将患者分组时，也观察到了显著差异。有趣的是，高 MN 频率的患者与低频率的患者相比，首次治疗的时间更短（P = 0.024）。与对照组相比，IGHV 状态突变和未突变的病例的 CA 和 MN 频率均增加（P ≤ 0.0007），但两组之间无差异。我们的结果支持 CIN 与基因组复杂性之间的强烈相互作用，以及它们对该病理学不良预后的影响。
