PDF(Pubmed)
Abstract：
Epithelial ovarian cancer (EOC) heavily relies on oxidative phosphorylation (OXPHOS) and exhibits distinct mitochondrial metabolic reprogramming. Up to now, the evolutionary pattern of somatic mitochondrial DNA (mtDNA) mutations in EOC tissues and their potential roles in metabolic remodelling have not been systematically elucidated.
Based on a large somatic mtDNA mutation dataset from private and public EOC cohorts (239 and 118 patients, respectively), we most comprehensively characterised the EOC-specific evolutionary pattern of mtDNA mutations and investigated its biological implication.
Mutational profiling revealed that the mitochondrial genome of EOC tissues was highly unstable compared with non-cancerous ovary tissues. Furthermore, our data indicated the delayed heteroplasmy accumulation of mtDNA control region (mtCTR) mutations and near-complete absence of mtCTR non-hypervariable segment (non-HVS) mutations in EOC tissues, which is consistent with stringent negative selection against mtCTR mutation. Additionally, we observed a bidirectional and region-specific evolutionary pattern of mtDNA coding region mutations, manifested as significant negative selection against mutations in complex V (ATP6/ATP8) and tRNA loop regions, and potential positive selection on mutations in complex III (MT-CYB). Meanwhile, EOC tissues showed higher mitochondrial biogenesis compared with non-cancerous ovary tissues. Further analysis revealed the significant association between mtDNA mutations and both mitochondrial biogenesis and overall survival of EOC patients.
Our study presents a comprehensive delineation of EOC-specific evolutionary patterns of mtDNA mutations that aligned well with the specific mitochondrial metabolic remodelling, conferring novel insights into the functional roles of mtDNA mutations in EOC tumourigenesis and progression.
Based on a large somatic mtDNA mutation dataset from private and public EOC cohorts (239 and 118 patients, respectively), we most comprehensively characterised the EOC-specific evolutionary pattern of mtDNA mutations and investigated its biological implication.
Mutational profiling revealed that the mitochondrial genome of EOC tissues was highly unstable compared with non-cancerous ovary tissues. Furthermore, our data indicated the delayed heteroplasmy accumulation of mtDNA control region (mtCTR) mutations and near-complete absence of mtCTR non-hypervariable segment (non-HVS) mutations in EOC tissues, which is consistent with stringent negative selection against mtCTR mutation. Additionally, we observed a bidirectional and region-specific evolutionary pattern of mtDNA coding region mutations, manifested as significant negative selection against mutations in complex V (ATP6/ATP8) and tRNA loop regions, and potential positive selection on mutations in complex III (MT-CYB). Meanwhile, EOC tissues showed higher mitochondrial biogenesis compared with non-cancerous ovary tissues. Further analysis revealed the significant association between mtDNA mutations and both mitochondrial biogenesis and overall survival of EOC patients.
Our study presents a comprehensive delineation of EOC-specific evolutionary patterns of mtDNA mutations that aligned well with the specific mitochondrial metabolic remodelling, conferring novel insights into the functional roles of mtDNA mutations in EOC tumourigenesis and progression.
摘要：
背景：上皮性卵巢癌（EOC）严重依赖氧化磷酸化（OXPHOS）并表现出明显的线粒体代谢重编程。到目前为止,EOC组织中体细胞线粒体DNA（mtDNA）突变的进化模式及其在代谢重塑中的潜在作用尚未得到系统阐明。
方法：基于来自私人和公共EOC队列（239和118名患者，分别)，我们最全面地描述了mtDNA突变的EOC特异性进化模式，并研究了其生物学意义。
结果：突变分析显示，与非癌性卵巢组织相比，EOC组织的线粒体基因组高度不稳定。此外，我们的数据表明，在EOC组织中mtDNA控制区（mtCTR）突变的延迟异质积累和mtCTR非高变段（非HVS）突变的几乎完全缺失，这与针对mtCTR突变的严格阴性选择一致。此外,我们观察到mtDNA编码区突变的双向和区域特异性进化模式，表现为针对复杂V（ATP6/ATP8）和tRNA环区突变的显着负选择，以及对复合物III（MT-CYB）突变的潜在正选择。同时,与非癌性卵巢组织相比，EOC组织显示出更高的线粒体生物发生。进一步的分析显示，mtDNA突变与线粒体生物发生和EOC患者的总体生存率之间存在显着关联。
结论：我们的研究全面描述了EOC特异性mtDNA突变的进化模式，该模式与特定的线粒体代谢重塑吻合良好。为mtDNA突变在EOC肿瘤发生和发展中的功能作用提供了新的见解。
方法：基于来自私人和公共EOC队列（239和118名患者，分别)，我们最全面地描述了mtDNA突变的EOC特异性进化模式，并研究了其生物学意义。
结果：突变分析显示，与非癌性卵巢组织相比，EOC组织的线粒体基因组高度不稳定。此外，我们的数据表明，在EOC组织中mtDNA控制区（mtCTR）突变的延迟异质积累和mtCTR非高变段（非HVS）突变的几乎完全缺失，这与针对mtCTR突变的严格阴性选择一致。此外,我们观察到mtDNA编码区突变的双向和区域特异性进化模式，表现为针对复杂V（ATP6/ATP8）和tRNA环区突变的显着负选择，以及对复合物III（MT-CYB）突变的潜在正选择。同时,与非癌性卵巢组织相比，EOC组织显示出更高的线粒体生物发生。进一步的分析显示，mtDNA突变与线粒体生物发生和EOC患者的总体生存率之间存在显着关联。
结论：我们的研究全面描述了EOC特异性mtDNA突变的进化模式，该模式与特定的线粒体代谢重塑吻合良好。为mtDNA突变在EOC肿瘤发生和发展中的功能作用提供了新的见解。
