Richard S M, Bailliet G, Páez G L, Bianchi M S, Peltomäki P, Bianchi N O
Instituto Multidisciplinario de Biología Celular, La Plata, Argentina.
Cancer Res. 2000 Aug 1;60(15):4231-7.
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.
我们分析了40对乳腺正常/癌组织，以检测肿瘤细胞中线粒体（mt）基因组不稳定性和核微卫星不稳定性（MSI）。作为mt标记，我们使用了一个从D环区域514 bp位置起始的(CA)n mt微卫星（MS），以及位于D环区域16,108至16,420 bp位置之间的4个信息丰富的MnlI位点。使用8个(CA)n MS检测核微卫星不稳定性（MSI），这些MS与13号染色体臂同线。此外，我们检测了459个母/子事件中mtMSI和mt-MnlI突变的自发频率。在40个乳腺肿瘤中有19个（47.5%）发现了mt-MnlI位点突变，这比女性生殖系中的自发率增加了216倍。40个乳腺癌中有17个（42.5%）发生了mtMS不稳定性，这意味着比自发突变率增加了16倍。40个病例中有20个（50%）发现了核MSI。在这些病例中，15个病例的MSI仅限于一个位点，而在5个病例中，在2个或3个位点检测到等位基因变化。mt与核突变之间的相关性分析未显示出显著关联，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。我们提出，产生mtRFLP和mtMSI的两个主要机制是自由基损伤和聚合酶γ的错误修复，第一个机制是MnlI突变的主要原因和mtMSI的次要原因。
