DataSheet2_Methylation-related genes involved in renal carcinoma progression.zip

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与死亡病例中占较大比例。明确驱动肾细胞癌进展的分子机制，对于开发靶向治疗策略、改善患者预后具有关键意义。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潜在驱动因素。已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。此类机制通常可与不同的表观遗传标记相关联，例如DNA甲基化位点或染色质构象模式。目前，尚无明确方法可厘清影响癌症进展的遗传与表观遗传因素间的清晰关联。本研究中，我们开发了一种数据驱动的方法以筛选甲基化相关基因，借此得以明确透明细胞肾细胞癌（clear cell renal carcinoma, ccRC）进展过程中，调控生物学进程的基因共表达与全基因组甲基化调控模式间的关键关联。通过该方法，我们发现了ITK癌基因等一批基因：它们在透明细胞肾细胞癌进展的全部四个阶段均呈现低甲基化状态，并与免疫应答功能密切相关。此外，我们还鉴定出RAB25等相关抑癌基因，其呈现高甲基化状态，这可能会在透明细胞肾细胞癌演进过程中，解除AKT信号通路（AKT signaling pathway）中被抑制的功能。本研究结果对于进一步阐释肾细胞癌进展过程中受表观遗传-遗传调控的相关机制具有重要价值。