Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity
Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity
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DOI：
10.1073/pnas.090013497
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发表时间：
2000-05-09
影响因子：
11.1
通讯作者：
Mandahl, N
中科院分区：
文献类型：
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作者：
Gisselsson, D;Pettersson, L;Mandahl, N
人们早就知道，通过断裂-融合-桥（BFB）循环的染色体重排可能会导致细胞群体内表型和遗传性状的变异。由于细胞间异质性通常存在于肿瘤组织中，我们研究了BFB事件在人类实体瘤中的发生。在显示非特异性染色体畸变（包括环状染色体、双着丝粒染色体和端粒缔合）以及结构变化模式的广泛瘤内异质性的恶性肿瘤中发现了频繁BFB事件的证据，但在具有肿瘤特异性畸变和低变异性的肿瘤中未发现。荧光原位杂交分析表明，参与后期桥形成的染色体比其他染色体参与了显着较高的数量的结构畸变。与正常细胞和其他肿瘤细胞相比，具有BFB事件的肿瘤显示出照射后不稳定染色体畸变的消除率降低。该结果表明，有丝分裂不稳定的染色体和对染色体损伤的耐受性提高的组合导致许多恶性肿瘤中的恒定基因组重组，从而为克隆进化和进展提供了灵活的遗传系统。
It has long been known that rearrangements of chromosomes through breakage-fusion-bridge (BFB) cycles may cause variability of phenotypic and genetic traits within a cell population. Because intercellular heterogeneity is often found in neoplastic tissues, we investigated the occurrence of BFB events in human solid tumors. Evidence of frequent BFB events was found in malignancies that showed unspecific chromosome aberrations, including ring chromosomes, dicentric chromosomes, and telomeric associations, as well as extensive intratumor heterogeneity in the pattern of structural changes but not in tumors with tumor-specific: aberrations and low variability. Fluorescence in situ hybridization analysis demonstrated that chromosomes participating in anaphase bridge formation were involved in a significantly higher number of structural aberrations than other chromosomes. Tumors with BFB events showed a decreased elimination rate of unstable chromosome aberrations after irradiation compared with normal cells and other tumor cells. This result suggests that a combination of mitotically unstable chromosomes and an elevated tolerance to chromosomal damage leads to constant genomic reorganization in many malignancies, thereby providing a flexible genetic system for clonal evolution and progression.