Table1_Methylation-related genes involved in renal carcinoma progression.XLSX

Renal carcinomas are a group of malignant tumors often originating in the cells lining the small tubes in the kidney responsible for filtering waste from the blood and urine production. Kidney tumors arise from the uncontrolled growth of cells in the kidneys and are responsible for a large share of global cancer-related morbidity and mortality. Understanding the molecular mechanisms driving renal carcinoma progression results crucial for the development of targeted therapies leading to an improvement of patient outcomes. Epigenetic mechanisms such as DNA methylation are known factors underlying the development of several cancer types. There is solid experimental evidence of relevant biological functions modulated by methylation-related genes, associated with the progression of different carcinomas. Those mechanisms can often be associated to different epigenetic marks, such as DNA methylation sites or chromatin conformation patterns. Currently, there is no definitive method to establish clear relations between genetic and epigenetic factors that influence the progression of cancer. Here, we developed a data-driven method to find methylation-related genes, so we could find relevant bonds between gene co-expression and methylation-wide-genome regulation patterns able to drive biological processes during the progression of clear cell renal carcinoma (ccRC). With this approach, we found out genes such as ITK oncogene that appear hypomethylated during all four stages of ccRC progression and are strongly involved in immune response functions. Also, we found out relevant tumor suppressor genes such as RAB25 hypermethylated, thus potentially avoiding repressed functions in the AKT signaling pathway during the evolution of ccRC. Our results have relevant implications to further understand some epigenetic–genetic-affected roles underlying the progression of renal cancer.

肾细胞癌（Renal Carcinomas）是一类恶性肿瘤，通常起源于肾脏内负责过滤血液废物、生成尿液的小管内衬细胞。肾脏肿瘤由肾脏细胞不受控增殖引发，在全球癌症相关发病率与死亡率中占据较高比例。阐明驱动肾细胞癌进展的分子机制，对于开发靶向治疗方案、改善患者预后至关重要。表观遗传机制（Epigenetic Mechanisms）如DNA甲基化（DNA Methylation），已被证实是多种癌症发生发展的关键诱因。现有可靠实验证据表明，甲基化相关基因所调控的生物学功能，与多种癌症的进展密切相关。这类调控机制通常与不同的表观遗传标记相关，例如DNA甲基化位点（DNA Methylation Sites）或染色质构象模式（Chromatin Conformation Patterns）。目前尚无明确方法可系统阐明影响癌症进展的遗传与表观遗传因素之间的清晰关联。本研究开发了一种数据驱动的甲基化相关基因筛选方法，以期明确透明细胞肾细胞癌（Clear Cell Renal Carcinoma, ccRC）进展过程中，驱动生物学过程的基因共表达与全基因组甲基化调控模式之间的关键关联。通过该方法，我们鉴定出ITK癌基因（ITK Oncogene）等基因，这类基因在透明细胞肾细胞癌的四个进展阶段均呈现低甲基化状态，且与免疫应答功能密切相关。同时，本研究还发现RAB25等抑癌基因存在高甲基化现象，该甲基化状态或可解除AKT信号通路（AKT Signaling Pathway）所受的功能抑制。本研究结果对于进一步阐明肾癌进展过程中受表观遗传-遗传交互调控的相关机制具有重要参考价值。