Zamora-Fuentes Jose María, Hernández-Lemus Enrique, Espinal-Enríquez Jesús
Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.
Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Front Genet. 2023 Aug 25;14:1225158. doi: 10.3389/fgene.2023.1225158. eCollection 2023.
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.
肾癌是一组恶性肿瘤，通常起源于肾脏中负责过滤血液中的废物和产生尿液的小管内衬细胞。肾肿瘤源于肾脏细胞的不受控制的生长，在全球癌症相关的发病率和死亡率中占很大比例。了解驱动肾癌进展的分子机制对于开发靶向治疗以改善患者预后至关重要。诸如DNA甲基化等表观遗传机制是几种癌症类型发生的已知因素。有确凿的实验证据表明，甲基化相关基因调节的相关生物学功能与不同癌症的进展有关。这些机制通常可以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，尚无确定的方法来建立影响癌症进展的遗传和表观遗传因素之间的明确关系。在这里，我们开发了一种数据驱动的方法来寻找甲基化相关基因，以便我们能够找到基因共表达与全基因组甲基化调控模式之间的相关联系，这些模式能够在透明细胞肾癌（ccRC）进展过程中驱动生物学过程。通过这种方法，我们发现了诸如ITK癌基因等基因，这些基因在ccRC进展的所有四个阶段都表现出低甲基化，并且强烈参与免疫反应功能。此外，我们还发现了相关的肿瘤抑制基因，如RAB25高甲基化，从而可能避免在ccRC发展过程中AKT信号通路中的功能受到抑制。我们的结果对于进一步理解肾癌进展背后的一些表观遗传-遗传影响的作用具有重要意义。
