Li Tengda, Gu Mingli, Deng Anmei, Qian Cheng
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020 China.
Department of Laboratory Diagnosis, Changhai Hospital, The Second Military Medical University, Shanghai, 200433 China.
Cancer Cell Int. 2020 Jun 15;20:239. doi: 10.1186/s12935-020-01309-5. eCollection 2020.
The incidence and mortality of melanoma is increasing around the world. To deeply explain the mechanism insight into it, we conducted a systematic analysis to examine the levels of regulatory genes of the common RNA epigenetic modification-N6-methyladenosine (mA) in patients with melanoma compared by the healthy.
We analyzed the expression of mA Eraser, Writer, and Reader genes based on publicly available datasets on Oncomine and validated the results with a gene expression omnibus dataset. Hub genes were identified with Cytohubba and the frequency of copy number alterations was analyzed with the cBioPortal tool.
The results revealed the up-regulation of YTHDF1 and HNRNPA2B1 in melanoma. Combining the two genes improved the efficacy in diagnosing melanoma by about 10% compared to each gene alone. Hub genes identified with four analysis methods were compared and the overlapping genes were selected. These genes were enriched in several gene ontology terms. Genes related to p53-signaling consisted of CDK2, CDK1, RRM2, CCNB1, and CHEK1. All five genes were positively correlated with either YTHDF1 or HNRNPA2B1, suggesting that both genes may affect mA modification by the five genes, further up-regulating their expression and facilitate their roles in inhibiting p53 to suppress tumorigenesis. We also observed major mutations in YTHDF1 and HNRNPA2B1 that led to their amplification in melanoma. Significant differences were observed in the clinical characteristics of patients with altered and unaltered mA regulatory genes such as tumor stage and treatment response.
We, for the first time, identified a combination of mA regulatory genes to diagnose melanoma. We also analyzed mA-related genes more comprehensively based on systematic complete data. We found that YTHDF1 and HNRNPA2B1 were altered in melanoma and might influence the development of the disease through signaling pathways such as p53.
黑色素瘤的发病率和死亡率在全球范围内呈上升趋势。为深入解释其发病机制，我们进行了一项系统分析，以研究黑色素瘤患者中常见RNA表观遗传修饰——N6-甲基腺苷（m⁶A）的调控基因水平，并与健康人进行比较。
我们基于Oncomine上的公开数据集分析了m⁶A去甲基化酶、甲基化转移酶和甲基化阅读蛋白基因的表达，并使用基因表达综合数据集验证了结果。通过Cytohubba鉴定枢纽基因，并使用cBioPortal工具分析拷贝数改变的频率。
结果显示黑色素瘤中YTHDF1和HNRNPA2B1上调。与单独使用每个基因相比，联合这两个基因诊断黑色素瘤的效能提高了约10%。比较了用四种分析方法鉴定的枢纽基因，并选择了重叠基因。这些基因在多个基因本体术语中富集。与p53信号通路相关的基因包括CDK2、CDK1、RRM2、CCNB1和CHEK1。所有这五个基因均与YTHDF1或HNRNPA2B1呈正相关，表明这两个基因可能通过这五个基因影响m⁶A修饰，进一步上调它们的表达，并促进它们在抑制p53以抑制肿瘤发生中的作用。我们还观察到YTHDF1和HNRNPA2B1的主要突变导致它们在黑色素瘤中扩增。在m⁶A调控基因改变和未改变的患者的临床特征（如肿瘤分期和治疗反应）方面观察到显著差异。
我们首次鉴定出一组用于诊断黑色素瘤的m⁶A调控基因组合。我们还基于系统完整的数据更全面地分析了与m⁶A相关的基因。我们发现YTHDF1和HNRNPA2B1在黑色素瘤中发生改变，并可能通过p53等信号通路影响疾病的发展。
