Song Kaiyang, Artibani Mara
Green Templeton College University of Oxford Oxford UK.
Ovarian Cancer Cell Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine University of Oxford Oxford UK.
Health Sci Rep. 2023 Apr 27;6(5):e1235. doi: 10.1002/hsr2.1235. eCollection 2023 May.
Ovarian cancer (OC) is the most lethal gynecological cancer. In 2018, it was responsible for over 180,000 deaths worldwide. The high mortality rate is the culmination of a lack of early diagnosis and high rates of chemotherapy resistance, which is synonymous with disease recurrence. Over the last two decades, an increasingly significant role of epigenetic mechanisms, in particular DNA methylation, has emerged. This review will discuss several of the most significant genes whose hypo/hypermethylation profiles are associated with chemoresistance. Aside from functionally elucidating and evaluating these epimutations, this review will discuss recent trials of DNA methyltransferase inhibitors (DNMTi). Finally, we will propose future directions that could enhance the feasibility of utilizing these candidate epimutations as clinical biomarkers.
To perform this review, a comprehensive literature search based on our keywords was conducted across the online databases PubMed and Google Scholar for identifying relevant studies published up until August 2022.
Epimutations affecting MLH1, MSH2, and Ras-association domain family 1 isoform A (DNA damage repair and apoptosis); ATP-binding cassette subfamily B member 1 and methylation-controlled J (drug export); secreted frizzled-related proteins (Wnt/β-catenin signaling), neurocalcin delta (calcium and G protein-coupled receptor signaling), and zinc finger protein 671 all have potential as biomarkers for chemoresistance. However, specific uncertainties relating to these epimutations include histotype-specific differences, intrinsic versus acquired chemoresistance, and the interplay with complete surgical debulking. DNMTi for chemoresistant OC patients has shown some promise; however, issues surrounding their efficacy and dose-limiting toxicities remain; a personalized approach is required to maximize their effectiveness.
Establishing a panel of aberrantly methylated chemoresistance-related genes to predict chemoresponsiveness and patients' suitability to DNMTi could significantly reduce OC recurrence, while improving DNMTi therapy viability. To achieve this, a large-scale prospective genome-wide DNA methylation profile study that spans different histotypes, includes paired samples (before and after chemotherapy), and integrates transcriptomic and methylomic analysis, is warranted.
卵巢癌（OC）是最致命的妇科癌症。2018年，全球有超过18万人死于该病。高死亡率是缺乏早期诊断以及化疗耐药率高的结果，而化疗耐药与疾病复发同义。在过去二十年中，表观遗传机制，尤其是DNA甲基化，发挥着越来越重要的作用。本综述将讨论几个最重要的基因，其低甲基化/高甲基化谱与化疗耐药相关。除了从功能上阐明和评估这些表观突变外，本综述还将讨论DNA甲基转移酶抑制剂（DNMTi）的近期试验。最后，我们将提出未来的方向，以提高将这些候选表观突变用作临床生物标志物的可行性。
为进行本综述，在在线数据库PubMed和谷歌学术上基于我们的关键词进行了全面的文献检索，以识别截至2022年8月发表的相关研究。
影响错配修复蛋白1（MLH1）、错配修复蛋白2（MSH2）和Ras关联结构域家族1同工型A（DNA损伤修复和凋亡）；ATP结合盒亚家族B成员1和甲基化调控蛋白J（药物外排）；分泌型卷曲相关蛋白（Wnt/β-连环蛋白信号通路）、神经钙蛋白δ（钙和G蛋白偶联受体信号通路）以及锌指蛋白671的表观突变均有作为化疗耐药生物标志物的潜力。然而，与这些表观突变相关的具体不确定性包括组织学类型特异性差异、内在耐药与获得性耐药，以及与完全手术减瘤的相互作用。用于化疗耐药OC患者的DNMTi已显示出一些前景；然而，围绕其疗效和剂量限制性毒性的问题仍然存在；需要采用个性化方法以使其有效性最大化。
建立一组异常甲基化的化疗耐药相关基因以预测化疗反应性和患者对DNMTi的适用性，可显著降低OC复发率，同时提高DNMTi治疗的可行性。要实现这一点，有必要开展一项大规模前瞻性全基因组DNA甲基化谱研究，该研究涵盖不同组织学类型，包括配对样本（化疗前后），并整合转录组学和甲基组学分析。
