DataSheet4_Systematic Investigation of DNA Methylation Associated With Platinum Chemotherapy Resistance Across 13 Cancer Types.PDF

Background: 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. Methods: 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. Results: A total of 3,703 DMPs (p 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 p 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. Conclusion: 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.背景：铂类耐药是肿瘤临床医师面临的重大挑战，因此近年来表观遗传学（epigenetics）与DNA甲基化（DNA methylation）在铂类化疗耐药中的作用日益受到研究者的广泛关注，亟需开展针对多种癌症类型中与铂类耐药相关的异常甲基化模式的系统性研究。 方法：本研究对13种癌症类型共618例患者的铂类化疗应答相关甲基化模式进行多维度分析，并整合了转录组与临床数据。采用斯皮尔曼检验（Spearman’s test）评估甲基化水平与基因表达的相关性；通过Cox分析、Kaplan-Meier法及对数秩检验（log-rank tests），基于差异甲基化位点（differentially methylated positions, DMPs）筛选潜在风险生物标志物，并依据DMP值比较患者生存情况。采用支持向量机（Support vector machines）与受试者工作特征曲线（receiver operating characteristic curves）筛选可预测铂类化疗应答的DMPs。 结果：本研究共鉴定出3703个DMPs（P值<0.001且绝对Δβ值>0.10），不同癌症类型的DMP数量存在差异。在铂类耐药患者中，39.83%的DMPs呈高甲基化状态，60.17%呈低甲基化状态。其中，405个经Benjamini和Hochberg校正后P值<0.05的DMPs与接受铂类方案治疗的肿瘤患者预后相关；另有664个DMPs具备预测铂类化疗应答的潜力。此外，本研究确定了由4个基因（间皮素、蛋白激酶cAMP依赖型II型调节亚基β、msh同源盒1、PAR-6家族细胞极性调节因子α）组成的6个DMPs，其可能对铂类化疗具有良好的预后与预测价值。 结论：甲基化-转录轴确实存在，并参与多种癌症中铂类耐药的复杂生物学机制。本研究鉴定的6个DMPs及其关联的4个基因有望成为铂类化疗的潜在表观遗传生物标志物，可为临床优化治疗方案选择提供指导。