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Abstract：
The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including AJAP1, HOXB9, MYH14, and SLC6A19, which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment.
摘要：
肿瘤微环境(TME)在肿瘤的发展中起着至关重要的作用。转移,和对免疫疗法的反应。DNA甲基化可以调节TME而不改变DNA序列。然而,在肾透明细胞癌（ccRCC）中，甲基化驱动的TME的研究仍然缺乏。在这项研究中,整合的DNA甲基化和RNA-seq数据用于探索甲基化驱动基因(MDG).使用估算值计算免疫评分，用于鉴定TME相关基因。使用单变量与甲基化调节的TME相关的新特征，建立多变量Cox回归和LASSO回归分析。该签名包括四个TME-MDG，包括AJAP1，HOXB9，MYH14和SLC6A19，在肿瘤中表现出高甲基化和低表达。使用qRT-PCR进行验证,其证实它们在ccRCC临床样品中的下调。此外,该特征在ccRCC的不同亚型中表现出稳定的预测性能。风险评分与TMN分期呈正相关，免疫细胞浸润，肿瘤突变负荷，以及免疫治疗的不良后果。有趣的是,4种TME-MDG的表达与一线药物在ccRCC治疗中的敏感性高度相关，尤其是帕唑帕尼.分子对接表明蛋白质和帕唑帕尼之间的高亲和力结合。总之,我们的研究阐明了甲基化驱动的TME在ccRCC中的综合作用，帮助识别对免疫治疗和靶向治疗敏感的患者，为ccRCC治疗提供新的治疗靶点。
