Khadka Pabitra, Young Carolyn K J, Sachidanandam Ravi, Brard Laurent, Young Matthew J
Department of Biomedical Sciences, Division of Biochemistry & Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL, United States.
Girihlet Inc, Oakland, CA, United States.
Front Oncol. 2024 Jun 27;14:1394699. doi: 10.3389/fonc.2024.1394699. eCollection 2024.
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.
子宫内膜癌（EC）是一种影响女性健康的常见且具有破坏性的疾病。美国国立癌症研究所的监测、流行病学和最终结果计划预测，2023年美国将有超过66000例子宫内膜癌新发病例，超过13000人死于该病，并且子宫内膜癌是全球女性中第六大常见癌症。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、脂质、核苷酸和葡萄糖的生物合成提供必要的组成部分。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基因组是一种对脊椎动物生命至关重要的环状双链分子，它包含对氧化磷酸化至关重要的基因以及线粒体衍生肽基因。癌细胞表现出有氧糖酵解，即瓦伯格效应，这源于快速分裂细胞的需求，其特征是葡萄糖摄取增加以及葡萄糖转化为乳酸。实体瘤通常至少含有一个mtDNA替代。此外，癌细胞含有野生型和突变型mtDNA基因型的混合物，即异质性，这很常见。考虑到癌细胞能量需求的增加，癌症中存在功能相关的致癌或适应环境的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个子宫内膜癌肿瘤特异性mtDNA单核苷酸变体。存在许多指示易出错的DNA聚合酶γ复制和C到U脱氨事件的转换突变。我们研究了突变谱及其异质性，并讨论了复发性、非同义、插入和缺失突变的潜在生物学影响。最后，我们探讨了当前子宫内膜癌的治疗方法、利用癌细胞线粒体进行治疗以及将mtDNA变体用作子宫内膜癌生物标志物的前景。
