Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.
Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.
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DOI：
10.7554/elife.02935
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发表时间：
2014-10-01
期刊：
影响因子：
7.7
通讯作者：
Campbell PJ
中科院分区：
文献类型：
--
作者：
Ju YS;Alexandrov LB;Gerstung M;Martincorena I;Nik-Zainal S;Ramakrishna M;Davies HR;Papaemmanuil E;Gundem G;Shlien A;Bolli N;Behjati S;Tarpey PS;Nangalia J;Massie CE;Butler AP;Teague JW;Vassiliou GS;Green AR;Du MQ;Unnikrishnan A;Pimanda JE;Teh BT;Munshi N;Greaves M;Vyas P;El-Naggar AK;Santarius T;Collins VP;Grundy R;Taylor JA;Hayes DN;Malkin D;ICGC Breast Cancer Group;ICGC Chronic Myeloid Disorders Group;ICGC Prostate Cancer Group;Foster CS;Warren AY;Whitaker HC;Brewer D;Eeles R;Cooper C;Neal D;Visakorpi T;Isaacs WB;Bova GS;Flanagan AM;Futreal PA;Lynch AG;Chinnery PF;McDermott U;Stratton MR;Campbell PJ
最近的测序研究已经广泛地探索了癌症的核基因组中存在的体细胞改变。虽然线粒体控制能量代谢和细胞凋亡，但mtDNA中癌症相关突变的起源和影响尚不清楚。在这项研究中，我们分析了1675个肿瘤mtDNA的体细胞改变。我们鉴定了1907个体细胞置换，其表现出显著的复制链偏好，在线粒体重链上主要是C> T和A> G。这种链不对称特征不同于在核癌症基因组中发现的那些，但与推断的形成灵长类动物mtDNA序列内容的生殖系过程相匹配。许多mtDNA突变在肿瘤类型中表现出相当大的异质性。错义突变是选择性中性的，并且通常随着时间的推移逐渐趋向同质性。相反，导致蛋白质截短的突变经历负选择并且几乎完全是异质的。我们的研究结果表明，内源性突变机制的影响远远大于任何其他外部诱变剂在线粒体，并从根本上与mtDNA复制。DOI：www.example.com当一个细胞分裂产生两个新细胞时，细胞核中的DNA必须被忠实地复制，并平均地分裂。在复制过程中有时会产生错误或突变，而突变也可以通过将DNA暴露于被称为诱变剂的破坏剂（如紫外线或香烟烟雾）中来引入。然后这些突变在细胞的所有后代中保持。这些突变中的大多数对细胞的特征没有影响（“乘客突变”）。然而，允许细胞不受控制地分裂并扩散到身体其他部位的“驱动突变”可能导致癌症。线粒体是负责产生细胞生存所需能量的细胞隔室，也负责启动程序性细胞死亡。线粒体含有它们自己的DNA--与细胞核中的DNA完全分离--它编码能量产生所必需的蛋白质。线粒体DNA分子经常暴露于由线粒体产生的称为活性氧的破坏性分子。因此，这些活性氧被认为是线粒体DNA突变的最重要原因之一。此外，由于癌细胞产生能量的方式与正常细胞不同，线粒体DNA中改变线粒体产生能量的能力的突变通常被认为有助于正常细胞癌变。然而，癌症和线粒体DNA突变之间的联系缺乏确凿的证据。Ju等人检查了从三十多种不同类型癌症的1675份癌症活检中提取的线粒体DNA序列，并将其与同一患者的正常组织进行了比较。这揭示了从癌细胞中提取的线粒体DNA中的1907个突变。突变的模式表明，大多数突变不是由活性氧引入的，而是由线粒体本身在细胞分裂时复制DNA的过程中产生的错误引起的。出乎意料的是，已知的诱变剂，如香烟烟雾或紫外线，对线粒体DNA突变的影响可以忽略不计。与传统观点相反，Ju等人没有发现线粒体DNA突变有助于癌症发展或扩散的证据。相反，就像在细胞核DNA中发现的乘客突变一样，大多数线粒体基因组突变没有明显的影响。然而，Ju等人发现，损害正常线粒体活性的DNA突变不太可能在癌细胞中维持。据推测，含有这些蛋白质的线粒体产生的能量较少，因此含有太多这些突变的细胞将更难生存。这表明，即使是癌细胞也必须有足够的正常功能的线粒体。DOI：www.example.com网站
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication. DOI: http://dx.doi.org/10.7554/eLife.02935.001 The DNA in a cell's nucleus must be copied faithfully, and divided equally, when a cell divides to produce two new cells. Mistakes—or mutations—are sometimes made during the copying process, and mutations can also be introduced by exposing DNA to damaging agents known as mutagens, such as UV light or cigarette smoke. These mutations are then maintained in all of the descendants of the cell. Most of these mutations have no impact on the cell's characteristics (‘passenger mutations’). However, ‘driver mutations’ that allow cells to divide uncontrollably and spread to other body sites can lead to cancer. Mitochondria are cellular compartments that are responsible for generating the energy a cell needs to survive and are also responsible for initiating programmed cell death. Mitochondria contain their own DNA—entirely separate from that in the nucleus of the cell—that encodes the proteins most essential for energy production. Mitochondrial DNA molecules are frequently exposed to damaging molecules called reactive oxygen species that are produced by the mitochondria. Therefore, these reactive oxygen species have been thought to be one of the most important causes of mitochondrial DNA mutations. In addition, because cancer cells produce energy differently to normal cells, mutations in the mitochondrial DNA that change the ability of the mitochondria to produce energy have been conventionally thought to help normal cells to become cancerous. However, conclusive evidence for a link between cancer and mitochondrial DNA mutations is lacking. Ju et al. examined the mitochondrial DNA sequences taken from 1675 cancer biopsies from over thirty different types of cancer and compared these to normal tissue from the same patients. This revealed 1907 mutations in the mitochondrial DNA taken from the cancer cells. The pattern of the mutations suggests that the majority of the mutations are not introduced from reactive oxygen species, but from the errors the mitochondria themselves make in the process of duplicating their DNA when a cell divides. Unexpectedly, known mutagens, such as cigarette smoke or UV light, had a negligible effect on mitochondrial DNA mutations. Contrary to conventional wisdom, Ju et al. found no evidence that the mitochondrial DNA mutations help cancer to develop or spread. Instead, like passenger mutations found in the DNA in the cell nucleus, most mitochondrial genome mutations have no discernible effect. However, Ju et al. revealed that DNA mutations that damage normal mitochondrial activity are less likely to be maintained in cancer cells. Presumably, mitochondria containing these proteins produce less energy, and so a cell containing too many of these mutations will find it harder to survive. This shows that having enough correctly functioning mitochondria is essential for even cancer cells to thrive. DOI: http://dx.doi.org/10.7554/eLife.02935.002