Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors
Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors
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DOI：
10.1073/pnas.211357798
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发表时间：
2001-10-23
影响因子：
11.1
通讯作者：
Mandahl, N
中科院分区：
文献类型：
--
作者：
Gisselsson, D;Jonson, T;Mandahl, N
虽然在肿瘤中的染色体不稳定的机制已被描述在动物和体外模型，鲜为人知的是这些过程中man. To探索人类肿瘤的细胞遗传学演变，染色体断裂点配置文件构建了102胰腺癌和140骨肉瘤，两种肿瘤类型的特点是广泛的基因组不稳定。少数染色体改变的病例显示断裂点优先聚集于末端条带，而许多改变的肿瘤主要显示间质和着丝粒断裂点。末端断裂点频率与端粒TTAGGG重复长度呈负相关，并且端粒TTAGGG探针的荧光原位杂交一致地表明缩短的端粒和> 10%的染色体末端缺乏端粒信号。由于端粒功能障碍可能导致不稳定的环状和双着丝粒染色体的形成，因此也评价了有丝分裂像。在所有的情况下，发现后期桥，荧光原位杂交证明广泛的染色体结构重排，与末端转移酶检测显示在5-20%的间期细胞的DNA片段。不到2%的细胞显示坏死或凋亡的证据，端粒酶在大多数情况下表达。因此，端粒功能障碍可能通过胰腺癌和骨肉瘤中持续的桥断裂事件触发染色体片段化，导致肿瘤基因组的持续重组。端粒酶表达不足以完全稳定染色体补体，但可能对防止完全基因组退化和维持细胞存活至关重要。
Although mechanisms for chromosomal instability in tumors have been described in animal and in vitro models, little is known about these processes in man. To explore cytogenetic evolution in human tumors, chromosomal breakpoint profiles were constructed for 102 pancreatic carcinomas and 140 osteosarcomas, two tumor types characterized by extensive genomic instability. Cases with few chromosomal alterations showed a preferential clustering of breakpoints to the terminal bands, whereas tumors with many changes showed primarily interstitial and centromeric breakpoints. The terminal breakpoint frequency was negatively correlated to telomeric TTAGGG repeat length, and fluorescence in situ hybridization with telomeric TTAGGG probes consistently indicated shortened telomeres and > 10% of chromosome ends lacking telomeric signals. Because telomeric dysfunction may lead to formation of unstable ring and dicentric chromosomes, mitotic figures were also evaluated. Anaphase bridges were found in all cases, and fluorescence in situ hybridization demonstrated extensive structural rearrangements of chromosomes, with terminal transferase detection showing fragmented DNA in 5-20% o Interphase cells. Less than 2% of cells showed evidence of necrosis or apoptosis, and telomerase was expressed in the majority o cases. Telomeric dysfunction may thus trigger chromosomal fragmentation through persistent bridge-breakage events in pancreatic carcinomas and osteosarcomas, leading to a continuous reorganization of the tumor genome. Telomerase expression is not sufficient for completely stabilizing the chromosome complement but may be crucial for preventing complete genomic deterioration and maintaining cellular survival.