Division of Molecular and Forensic Genetics, Department of Forensic Medicine, Faculty of Medicine, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland.
Institute of Biological Problems of the North, Far-East Branch of the Russian Academy of Sciences, Magadan, Russia.
Hum Mutat. 2018 May;39(5):691-701. doi: 10.1002/humu.23402. Epub 2018 Jan 24.
So far, a reliable spectrum of mitochondrial DNA mutations in colorectal cancer cells is still unknown, and neither is their significance in carcinogenesis. Indeed, it remains debatable whether mtDNA mutations are "drivers" or "passengers" of colorectal carcinogenesis. Thus, we analyzed 200 mitogenomes from normal and cancer tissues of 100 colorectal cancer patients. Minority variant mutations were detected at the 1% level. We showed that somatic mutations frequently occur in colorectal cancer cells (75%) and are randomly distributed across the mitochondrial genome. Mutational signatures of somatic mitogenome mutations suggest that they might arise through nucleotide deamination due to oxidative stress. The majority of somatic mutations localized within the coding region (in positions not known from the human phylogeny) and was potentially pathogenic to cell metabolism. Further analysis suggested that the relaxation of negative selection in the mitogenomes of colorectal cancer cells may allow accumulation of somatic mutations. Thus, a shift in glucose metabolism from oxidative phosphorylation to glycolysis may create advantageous conditions for accumulation of mtDNA mutations. Considering the fact that the presence of somatic mtDNA mutations was not associated with any clinicopathological features, we suggested that mtDNA somatic mutations are "passengers" rather than the cause of colorectal carcinogenesis.
迄今为止，结直肠癌细胞中线粒体 DNA 突变的可靠谱仍不清楚，其在癌变中的意义也不清楚。事实上，线粒体 DNA 突变是结直肠癌发生的“驱动因素”还是“乘客”仍存在争议。因此，我们分析了 100 例结直肠癌患者的 200 个线粒体基因组的正常和肿瘤组织。在 1%的水平上检测到少数变体突变。我们表明体细胞突变经常发生在结直肠癌细胞中（75%），并且随机分布在线粒体基因组中。体细胞线粒体突变的突变特征表明，它们可能由于氧化应激引起的核苷酸脱氨而产生。大多数体细胞突变定位于编码区（在人类系统发育中未知的位置），可能对细胞代谢具有潜在的致病性。进一步的分析表明，结直肠癌细胞中线粒体基因组中负选择的放松可能允许体细胞突变的积累。因此，葡萄糖代谢从氧化磷酸化向糖酵解的转变可能为 mtDNA 突变的积累创造有利条件。考虑到体细胞 mtDNA 突变的存在与任何临床病理特征均无关，我们认为体细胞 mtDNA 突变是“乘客”而不是结直肠癌发生的原因。
