Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA.
Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA.
复制标题
DOI：
10.1038/s42255-021-00378-8
复制
发表时间：
2021-04
影响因子：
20.8
通讯作者：
Reznik, Ed
中科院分区：
文献类型：
--
作者：
Gorelick, Alexander N.;Kim, Minsoo;Chatila, Walid K.;La, Konnor;Hakimi, A. Ari;Berger, Michael F.;Taylor, Barry S.;Gammage, Payam A.;Reznik, Ed
线粒体DNA（mtDNA）编码氧化磷酸化（OXPHOS）所需的蛋白质亚基和翻译机制。在本研究中，我们使用重新利用的全外显子组测序数据证明，肿瘤中致病性mtDNA突变的发生率与最常见的癌症驱动基因中的突变率相当。我们确定OXPHOS复合物作为关键的决定因素，塑造跨肿瘤谱系的体细胞mtDNA突变模式。功能丧失突变以升高的速率特别是在复合物I中积累，并且通常出现在特定的均聚热点处。相反，复合体V耗尽所有非同义突变，表明ATP合成和线粒体膜电位耗散的损害是在负选择下。常见的截短突变和罕见的错义等位基因都与泛谱系转录程序相关，即使在mtDNA突变相对罕见的癌症类型中也是如此。线粒体DNA的致病性突变与结直肠癌患者总体生存率的显著增加相关，表明基因型和表型之间存在明确的功能关系。因此，线粒体基因组在许多癌症中经常和功能性地被破坏，对患者分层、预后和治疗开发具有重要意义。
Mitochondrial DNA (mtDNA) encodes protein subunits and translational machinery required for oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, in the present study we demonstrate that pathogenic mtDNA mutations arise in tumours at a rate comparable to those in the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumour lineages. Loss-of-function mutations accumulate at an elevated rate specifically in complex I and often arise at specific homopolymeric hotspots. In contrast, complex V is depleted of all non-synonymous mutations, suggesting that impairment of ATP synthesis and mitochondrial membrane potential dissipation are under negative selection. Common truncating mutations and rarer missense alleles are both associated with a pan-lineage transcriptional programme, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal cancer patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with major implications for patient stratification, prognosis and therapeutic development.
登录
查看更多内容
影响因子：
16.6
作者：
Hopkins JF;Sabelnykova VY;Weischenfeldt J;Simon R;Aguiar JA;Alkallas R;Heisler LE;Zhang J;Watson JD;Chua MLK;Fraser M;Favero F;Lawerenz C;Plass C;Sauter G;McPherson JD;van der Kwast T;Korbel J;Schlomm T;Bristow RG;Boutros PC
通讯作者：
Boutros PC
影响因子：
2.8
作者：
Horvath, Rita;Reilmann, Ralf;Klopstock, Thomas
通讯作者：
Klopstock, Thomas
与成年线粒体疾病有关的核和线粒体DNA突变的患病率。
影响因子：
11.2
作者：
Gorman GS;Schaefer AM;Ng Y;Gomez N;Blakely EL;Alston CL;Feeney C;Horvath R;Yu-Wai-Man P;Chinnery PF;Taylor RW;Turnbull DM;McFarland R
通讯作者：
McFarland R
影响因子：
2.8
作者：
Alston, Charlotte L.;Morak, Monika;Taylor, Robert W.
通讯作者：
Taylor, Robert W.
纪念斯隆·克特林癌症中心的精密医学：临床下一代测序实现下一代目标治疗试验。
影响因子：
7.4
作者：
Hyman DM;Solit DB;Arcila ME;Cheng DT;Sabbatini P;Baselga J;Berger MF;Ladanyi M
通讯作者：
Ladanyi M