State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
Mol Biol Evol. 2012 Apr;29(4):1255-61. doi: 10.1093/molbev/msr290. Epub 2011 Nov 29.
In accordance with the hypothesis that cancer formation is a process of somatic evolution driven by natural selection, signature of positive selection has been detected on a number of cancer-related nuclear genes. It remains, however, controversial whether a similar selective pressure has also acted on mitochondrial DNA (mtDNA), a small molecule in mitochondrion that may play an important role in tumorigenesis by altering oxidative phosphorylation. To better understand the mutational pattern on cancerous mtDNA and decipher the genetic signature left by natural selection, a total of 186 entire mitochondrial genomes of cancerous and adjacent normal tissues from 93 esophageal cancer patients were obtained and extensively studied. Our results revealed that the observed mutational pattern on the cancerous mtDNAs might be best explained as relaxation of negative selection. Taking into account an additional 1,235 cancerous (nearly) complete mtDNA sequences retrieved from the literature, our results suggested that the relaxed selective pressure was the most likely explanation for the accumulation of mtDNA variation in different types of cancer. This notion is in good agreement with the observation that aerobic glycolysis, instead of mitochondrial respiration, plays the key role in generating energy in cancer cells. Furthermore, our study provided solid evidence demonstrating that problems in some of the published cancerous mtDNA data adequately explained the previously contradictory conclusions about the selective pressure on cancer mtDNA, thus serving as a paradigm emphasizing the importance of data quality in affecting our understanding on the role of mtDNA in tumorigenesis.
根据癌症的形成是一个受自然选择驱动的体细胞进化过程的假说，在许多与癌症相关的核基因中已经检测到了正选择的特征。然而，线粒体 DNA（mtDNA）是否也受到了类似的选择压力，这仍然存在争议。mtDNA 是一种存在于线粒体中的小分子，通过改变氧化磷酸化，可能在肿瘤发生中发挥重要作用。为了更好地了解癌症 mtDNA 上的突变模式，并解读自然选择留下的遗传特征，我们从 93 名食管癌患者的 186 个癌症和相邻正常组织中获得了完整的线粒体基因组，并进行了广泛的研究。我们的研究结果表明，癌症 mtDNAs 上观察到的突变模式可能最好解释为负选择的放松。考虑到从文献中检索到的另外 1235 个癌症（几乎）完整的 mtDNA 序列，我们的结果表明，放松的选择压力最有可能解释不同类型癌症中 mtDNA 变异的积累。这一观点与有氧糖酵解而不是线粒体呼吸在癌细胞中产生能量的关键作用的观察结果是一致的。此外，我们的研究提供了确凿的证据，证明一些已发表的癌症 mtDNA 数据中的问题充分解释了先前关于癌症 mtDNA 选择压力的相互矛盾的结论，因此，这一研究强调了数据质量在影响我们对 mtDNA 在肿瘤发生中的作用的理解方面的重要性。
