子宫内膜癌是一种影响妇女健康的严重的常见疾病。NCI监控,流行病学,和最终结果计划预测,到2023年,美国将有>66,000例新病例和>13,000例EC死亡,而EC是全球女性中第六大最常见的癌症。线粒体代谢的调节在肿瘤发生中起作用。在增殖的癌细胞中,线粒体为氨基酸的生物合成提供了必要的构建块,脂质,核苷酸,和葡萄糖。导致线粒体活性改变的一种机制是线粒体DNA(mtDNA)突变。多倍体人类mtDNA基因组是脊椎动物生命必需的环状双链分子,具有对氧化磷酸化至关重要的基因加上线粒体衍生的肽基因。癌细胞显示有氧糖酵解,被称为Warburg效应,这是由于快速分裂的细胞的需要,其特征是葡萄糖摄取增加和葡萄糖转化为乳酸。实体肿瘤通常含有至少一个mtDNA取代。此外,癌细胞通常含有野生型和突变型mtDNA基因型的混合物,被称为异质体。考虑到癌细胞能源需求的增加,在癌症中存在功能相关的致癌作用诱导或环境适应性mtDNA突变似乎是合理的.我们回顾了来自不同研究的111名个体的279种EC肿瘤特异性mtDNA单核苷酸变体。存在许多过渡突变,表明易错的DNA聚合酶γ复制和C到U脱氨基事件。我们检查了突变谱及其异质性,并讨论了复发的潜在生物学影响,非同义词,插入,和缺失突变。最后,我们探索目前的EC治疗方法,利用癌细胞线粒体进行治疗以及使用mtDNA变体作为EC生物标志物的前景。
Endometrial cancer (EC) is a devastating and common disease affecting women\'s health. The NCI Surveillance, Epidemiology, and End Results Program predicted that there would be >66,000 new cases in the United States and >13,000 deaths from EC in 2023, and EC is the sixth most common cancer among women worldwide. Regulation of mitochondrial metabolism plays a role in tumorigenesis. In proliferating cancer cells, mitochondria provide the necessary building blocks for biosynthesis of amino acids, lipids, nucleotides, and glucose. One mechanism causing altered mitochondrial activity is mitochondrial DNA (mtDNA) mutation. The polyploid human mtDNA genome is a circular double-stranded molecule essential to vertebrate life that harbors genes critical for oxidative phosphorylation plus mitochondrial-derived peptide genes. Cancer cells display aerobic glycolysis, known as the Warburg effect, which arises from the needs of fast-dividing cells and is characterized by increased glucose uptake and conversion of glucose to lactate. Solid tumors often contain at least one mtDNA substitution. Furthermore, it is common for cancer cells to harbor mixtures of wild-type and mutant mtDNA genotypes, known as
heteroplasmy. Considering the increase in cancer cell energy demand, the presence of functionally relevant carcinogenesis-inducing or environment-adapting mtDNA mutations in cancer seems plausible. We review 279 EC tumor-specific mtDNA single nucleotide variants from 111 individuals from different studies. Many transition mutations indicative of error-prone DNA polymerase γ replication and C to U deamination events were present. We examine the spectrum of mutations and their
heteroplasmy and discuss the potential biological impact of recurrent, non-synonymous, insertion, and deletion mutations. Lastly, we explore current EC treatments, exploiting cancer cell mitochondria for therapy and the prospect of using mtDNA variants as an EC biomarker.