Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Carcinogenesis. 2020 Jul 10;41(6):761-768. doi: 10.1093/carcin/bgaa012.
N 6-methyladenosine (m6A) is an abundant modification in RNAs that affects RNA metabolism, and it is reported to be closely related to cancer occurrence and metastasis. In this study, we focused on evaluating the associations between genetic variants in m6A modification genes and the risk of esophageal squamous-cell carcinoma (ESCC). By integrating data of our previous genome-wide association studies and the predictions of several annotation tools, we identified a single nucleotide polymorphism, rs2416282 in the promoter of YTHDC2, that was significantly associated with the susceptibility of ESCC (odds ratio = 0.84, 95% CI: 0.77-0.92, P = 2.81 × 10-4). Through further functional experiments in vitro, we demonstrated that rs2416282 regulated YTHDC2 expression. Knockdown of YTHDC2 substantially promoted the proliferation rate of ESCC cells by affecting several cancer-related signaling pathways. Our results suggested that rs2416282 contributed to ESCC risk by regulating YTHDC2 expression. This study provided us a valuable insight into the roles of genetic variants in m6A modification genes for ESCC susceptibility and may contribute to the prevention of this disease in the future.
N6-甲基腺苷（m6A）是 RNA 中丰富的修饰物，它影响 RNA 代谢，据报道与癌症的发生和转移密切相关。在这项研究中，我们专注于评估 m6A 修饰基因中的遗传变异与食管鳞状细胞癌（ESCC）风险之间的关联。通过整合我们之前全基因组关联研究的数据和几个注释工具的预测，我们确定了 YTHDC2 启动子中的单核苷酸多态性 rs2416282 与 ESCC 的易感性显著相关（比值比=0.84，95%CI：0.77-0.92，P=2.81×10-4）。通过体外进一步的功能实验，我们证明 rs2416282 调节了 YTHDC2 的表达。通过影响几种与癌症相关的信号通路，YTHDC2 的敲低显著促进了 ESCC 细胞的增殖率。我们的结果表明，rs2416282 通过调节 YTHDC2 的表达导致 ESCC 风险增加。这项研究为我们提供了一个有价值的见解，即 m6A 修饰基因中的遗传变异对 ESCC 易感性的作用，并可能有助于未来预防这种疾病。
