Nuclear and mitochondrial genome instability in human breast cancer.
Nuclear and mitochondrial genome instability in human breast cancer.
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发表时间：
2000-08
期刊：
影响因子：
11.2
通讯作者：
Silvina M. Richard;G. Bailliet;Gerardo L. Páez;M. Bianchi;P. Peltomäki;Néstor O. Bianchi
中科院分区：
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作者：
Silvina M. Richard;G. Bailliet;Gerardo L. Páez;M. Bianchi;P. Peltomäki;Néstor O. Bianchi
我们分析了40对乳腺正常/癌组织中肿瘤细胞中线粒体（mt）基因组不稳定性和核MSI的存在。作为mt标记，我们使用了起始于D环区514-bp位置的（CA）n mt微卫星（MS）和位于D环区16，108-bp和16，420-bp位置之间的4个信息MnlI位点。用8（CA）n MS检测13 q染色体臂的核微卫星不稳定性（MSI），并检测459例母/子事件中mtMSI和mt-MnlI突变的自发频率。在40例乳腺肿瘤中发现19例（47.5%）mt-MnlI位点突变，比女性生殖系的自发率增加了216倍。40例乳腺癌中有17例（42.5%）发生了mtMS不稳定，这意味着自发突变率增加了16倍。40例中有20例（50%）出现核MSI。其中15例MSI局限于1个位点，5例MSI发生在2 ~ 3个位点。mt和核突变之间的相关性分析显示没有显著的关联，这表明不同的系统负责肿瘤细胞中mt和核基因组的不稳定性。我们建议，两个主要的机制产生mtRFLP和mtMSI的自由基和错误修复聚合酶γ的损伤，第一个机制是MnlI突变的主要原因和mtMSI的次要原因。
We analyzed 40 pairs of breast normal/cancer tissues for the presence of mitochondrial (mt) genome instability and nuclear MSI in tumor cells. As mt, markers we used a (CA)n mt microsatellite (MS) starting at the 514-bp position of the D loop region and 4 informative MnlI sites located between the 16,108- and 16,420-bp positions of the D loop region. Nuclear microsatallite instability (MSI) was tested with 8 (CA)n MS, syntenic for the 13q chromosome arm. Moreover, we tested the spontaneous frequency of mtMSI and mt-MnlI mutations in 459 mother/descendant events. Mutations of mt-MnlI sites were found in 19 of 40 (47.5%) breast tumors, representing a 216-fold increase over the spontaneous rate in the female germline. Instability of the mtMS occurred in 17 of 40 (42.5%) breast cancers, which implies a 16-fold increase over the rate of spontaneous mutations. Nuclear MSI was found in 20 of 40 (50%) cases. In 15 of these cases the MSI was restricted to one locus, whereas in 5 instances the change of alleles was detected in 2 or 3 loci. Analysis of the correlation between mt and nuclear mutations showed no significant associations, suggesting that different systems are responsible for mt and nuclear genome instability in tumor cells. We propose that the two main mechanisms producing mtRFLP and mtMSI are damage by free radicals and error repair by the polymerase gamma, the first mechanism being a major cause of MnlI mutations and a secondary cause of mtMSI.