Simultaneous generation of multiple mitochondrial DNA mutations in human prostate tumors suggests mitochondrial hyper-mutagenesis
Simultaneous generation of multiple mitochondrial DNA mutations in human prostate tumors suggests mitochondrial hyper-mutagenesis
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DOI：
10.1093/carcin/bgg102
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发表时间：
2003-09-01
期刊：
影响因子：
4.7
通讯作者：
Kadlubar, FF
中科院分区：
文献类型：
--
作者：
Chen, JJZ;Gokden, N;Kadlubar, FF
在人类肿瘤中经常报告多个体细胞线粒体DNA突变，但导致同质转化和在同一肿瘤细胞谱系中积累多个突变的过程仍然是一个谜。我们解决了可能的机制，负责多个线粒体（mt）DNA突变的产生，观察到在高频率的前列腺肿瘤使用敏感的mu-特异性PCR加上激光捕获显微切割。对控制区有多个mtDNA突变的前列腺肿瘤的分析表明，突变局限于局部，多个突变存在于相同的分子上，并且在同一肿瘤病变中共存一种以上的mtDNA突变物种。这些结果表明，在肿瘤进展过程中，mtDNA突变的过程异常迅速。在前列腺肿瘤细胞动力学的基础上，我们提出了一个独特的线粒体超诱变过程，可能是由细胞氧化应激介导的，以解释人类前列腺肿瘤中多个mtDNA突变的爆发。
Multiple somatic mitochondrial DNA mutations are frequently reported in human tumors, but the process leading to homoplasmic transformation and accumulation of multiple mutations in the same tumor cell lineage remains a mystery. We address possible mechanisms responsible for the generation of multiple mitochondrial (mt)DNA mutations observed in a high frequency of prostate tumors using sensitive mutant-specific PCR coupled with laser capture microdissection. Analysis of prostate tumors with multiple mtDNA mutations in the control region indicates that the mutations are locally confined, that the multiple mutations exist on the same molecules and that more than one mtDNA mutant species co-exists in the same neoplastic lesion. These results suggest an unusually rapid process in mtDNA mutagenesis during tumor progression. On the basis of prostate tumor cell kinetics, we propose a unique process of mitochondrial hyper-mutagenesis, probably mediated by cellular oxidative stress, to account for a burst of multiple mtDNA mutations in human prostate tumors.