Department of Mathematics and Statistics, Kennesaw State University, Kennesaw, GA 30144, USA.
J Hum Genet. 2010 Sep;55(9):605-12. doi: 10.1038/jhg.2010.76. Epub 2010 Jul 8.
Tumors frequently contain somatic mutations in the mitochondrial DNA (mtDNA). Whether these mutations have a causal function or are merely an effect is still unclear. As tumor formation is a type of somatic evolution, we examine the cancer mutation pattern for consistency with random forces or selection. We also compare the tumor mutation pattern to that observed in the population to gain insight on the mutation process in cancer. Among germline mtDNAs, all genes show strong deficiency in missense changes, reflecting negative selection during human history. In somatic cancer sequences, mtDNA genes show relaxed negative selection relative to germline, or mutation consistent with neutrality. NADH dehydrogenase subunit 3, cytochrome c oxidase subunit 3 and NADH dehydrogenase subunit 4 L in particular show cancer missense mutation rates 9-18 times that of germline. Bootstrap analysis shows cytochrome B to have cancer changes in positions of unusually high conservation, suggesting that tumors select for mutations in residues of high functionality. Strong negative selection was detected in mitochondrially encoded cytochrome c oxidase 1 (MTCO1), suggesting that tumor cells are dependent upon MTCO1 function. Common population polymorphisms were also frequently reported among somatic tumor mutations. The implication of these 'somatic polymorphisms' in tumor growth is discussed.
肿瘤中经常存在线粒体 DNA（mtDNA）的体细胞突变。这些突变是否具有因果功能，还是仅仅是一种影响，目前尚不清楚。由于肿瘤的形成是一种体细胞进化，我们检查癌症突变模式是否与随机力或选择一致。我们还将肿瘤突变模式与人群中观察到的模式进行比较，以了解癌症中突变过程。在种系 mtDNA 中，所有基因的错义变化都明显不足，反映了人类历史上的负选择。在体细胞癌症序列中，mtDNA 基因相对于种系表现出松弛的负选择，或者与中性一致的突变。NADH 脱氢酶亚单位 3、细胞色素 c 氧化酶亚单位 3 和 NADH 脱氢酶亚单位 4L 尤其显示出癌症错义突变率是种系的 9-18 倍。自举分析显示细胞色素 B 在高度保守位置的癌症变化，表明肿瘤选择高功能残基的突变。在线粒体编码的细胞色素 c 氧化酶 1（MTCO1）中检测到强烈的负选择，表明肿瘤细胞依赖于 MTCO1 功能。常见的群体多态性也经常在体细胞肿瘤突变中报道。讨论了这些“体细胞多态性”在肿瘤生长中的意义。
