Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14087-91. doi: 10.1073/pnas.1211502109. Epub 2012 Aug 13.
Somatic mtDNA mutations have been reported in some human tumors, but their spectrum in different malignancies and their role in cancer development remain incompletely understood. Here, we describe the breadth of somatic and inherited mutations across the mitochondrial genome by sequence analyses of paired tumor and normal tissue samples from 226 individuals with five types of cancer using whole-genome data generated by The Cancer Genome Atlas Research Network. The frequencies of deleterious tumor-specific somatic mutations found in mtDNA varied across tumor types, ranging from 13% of glioblastomas to 63% of rectal adenocarcinomas. Compared with inherited mtDNA variants, somatic mtDNA mutations were enriched for nonsynonymous vs. synonymous changes (93 vs. 15; P < 2.2E-16) and were predicted to functionally impact the encoded protein. Somatic missense mutations in tumors were distributed uniformly among the mitochondrial protein genes, but 65% of somatic truncating mutations occurred in NADH dehydrogenase 5. Analysis of staging data in colon and rectal cancers revealed that the frequency of damaging mitochondrial mutations is the same in stages I and IV tumors. In summary, these data suggest that damaging somatic mtDNA mutations occur frequently (13-63%) in these five tumor types and likely confer a selective advantage in oncogenesis.
体细胞 mtDNA 突变已在一些人类肿瘤中被报道，但它们在不同恶性肿瘤中的谱及其在癌症发展中的作用仍不完全清楚。在这里，我们描述了使用癌症基因组图谱研究网络生成的全基因组数据，对来自 226 名患有五种癌症的个体的配对肿瘤和正常组织样本进行序列分析，从而了解整个线粒体基因组中的体细胞和遗传突变的广泛性。在 mtDNA 中发现的有害肿瘤特异性体细胞突变的频率在不同的肿瘤类型中有所不同，从胶质母细胞瘤的 13%到直肠腺癌的 63%不等。与遗传的 mtDNA 变体相比，体细胞 mtDNA 突变在非同义与同义变化方面更为丰富（93 比 15；P<2.2E-16），并被预测对编码蛋白具有功能影响。肿瘤中的体细胞错义突变在线粒体蛋白基因中均匀分布，但 65%的体细胞截断突变发生在 NADH 脱氢酶 5 中。对结肠癌和直肠癌分期数据的分析表明，在 I 期和 IV 期肿瘤中，线粒体突变的频率是相同的。总之，这些数据表明，在这五种肿瘤类型中，有害的体细胞 mtDNA 突变频繁发生（13-63%），并可能在肿瘤发生中赋予选择优势。
