Sun Ruizheng, Du Chao, Li Jiaxin, Zhou Yanhong, Xiong Wei, Xiang Juanjuan, Liu Jiheng, Xiao Zhigang, Fang Li, Li Zheng
NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China.
Front Pharmacol. 2021 Apr 29;12:616529. doi: 10.3389/fphar.2021.616529. eCollection 2021.
Platinum resistance poses a significant problem for oncology clinicians. As a result, the role of epigenetics and DNA methylation in platinum-based chemoresistance has gained increasing attention from researchers in recent years. A systematic investigation of aberrant methylation patterns related to platinum resistance across various cancer types is urgently needed. We analyzed the platinum chemotherapy response-related methylation patterns from different perspectives of 618 patients across 13 cancer types and integrated transcriptional and clinical data. Spearman's test was used to evaluate the correlation between methylation and gene expression. Cox analysis, the Kaplan-Meier method, and log-rank tests were performed to identify potential risk biomarkers based on differentially methylated positions (DMPs) and compare survival based on DMP values. Support vector machines and receiver operating characteristic curves were used to identify the platinum-response predictive DMPs. A total of 3,703 DMPs ( value < 0.001 and absolute delta beta >0.10) were identified, and the DMP numbers of each cancer type varied. A total of 39.83% of DMPs were hypermethylated and 60.17% were hypomethylated in platinum-resistant patients. Among them, 405 DMPs (Benjamini and Hochberg adjusted value < 0.05) were found to be associated with prognosis in tumor patients treated with platinum-based regimens, and 664 DMPs displayed the potential to predict platinum chemotherapy response. In addition, we defined six DNA DMPs consisting of four gene members (mesothelin, protein kinase cAMP-dependent type II regulatory subunit beta, msh homeobox 1, and par-6 family cell polarity regulator alpha) that may have favorable prognostic and predictive values for platinum chemotherapy. The methylation-transcription axis exists and participates in the complex biological mechanism of platinum resistance in various cancers. Six DMPs and four associated genes may have the potential to serve as promising epigenetic biomarkers for platinum-based chemotherapy and guide clinical selection of optimal treatment.
铂耐药给肿瘤临床医生带来了重大问题。因此，近年来表观遗传学和DNA甲基化在铂类化疗耐药中的作用越来越受到研究人员的关注。迫切需要对各种癌症类型中与铂耐药相关的异常甲基化模式进行系统研究。我们从13种癌症类型的618例患者的不同角度分析了与铂化疗反应相关的甲基化模式，并整合了转录和临床数据。采用Spearman检验评估甲基化与基因表达之间的相关性。进行Cox分析、Kaplan-Meier法和对数秩检验，以基于差异甲基化位点（DMP）识别潜在的风险生物标志物，并根据DMP值比较生存率。使用支持向量机和受试者工作特征曲线来识别铂反应预测性DMP。共鉴定出3703个DMP（P值<0.001且绝对β差异>0.10），每种癌症类型的DMP数量各不相同。在铂耐药患者中，共有39.83%的DMP发生高甲基化，60.17%发生低甲基化。其中，405个DMP（Benjamini和Hochberg校正P值<0.05）被发现与接受铂类方案治疗的肿瘤患者的预后相关，664个DMP显示出预测铂化疗反应的潜力。此外，我们定义了由四个基因成员（间皮素、蛋白激酶cAMP依赖性II型调节亚基β、msh同源盒1和par-6家族细胞极性调节因子α）组成的六个DNA DMP，它们可能对铂化疗具有良好的预后和预测价值。甲基化-转录轴存在并参与了各种癌症中铂耐药的复杂生物学机制。六个DMP和四个相关基因可能有潜力作为有前景的表观遗传生物标志物用于铂类化疗，并指导临床选择最佳治疗方案。
