Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Carcinogenesis. 2020 Mar 13;41(1):8-17. doi: 10.1093/carcin/bgz165.
The N6-methyladenosine (m6A) modification plays important regulatory roles in gene expression, cancer occurrence and metastasis. Herein, we aimed to explore the association between genetic variants in m6A modification genes and susceptibility to colorectal cancer. We used logistic regression models to investigate the associations between candidate single-nucleotide polymorphisms (SNPs) in 20 m6A modification genes and colorectal cancer risk. The false discovery rate (FDR) method was used for multiple comparisons. Dual luciferase assays and RNA m6A quantifications were applied to assess transcriptional activity and measure m6A levels, respectively. We found that SND1 rs118049207 was significantly associated with colorectal cancer risk in a Nanjing population (odds ratio (OR) = 1.69, 95% confidence interval (95% CI) = 1.31-2.18, P = 6.51 × 10-6). This finding was further replicated in an independent Beijing population (OR = 1.36, 95% CI = 1.04-1.79, P = 2.41 × 10-2) and in a combined analysis (OR = 1.52, 95% CI = 1.27-1.84, P = 8.75 × 10-6). Stratification and interaction analyses showed that SND1 rs118049207 multiplicatively interacted with the sex and drinking status of the patients to enhance their colorectal cancer risk (P = 1.56 × 10-3 and 1.41 × 10-2, respectively). Furthermore, rs118049207 served as an intronic enhancer on SND1 driven by DMRT3. SND1 mRNA expression was markedly increased in colorectal tumour tissues compared with adjacent normal tissues. The colorimetric m6A quantification strategy revealed that SND1 could alter m6A levels in colorectal cancer cell lines. Our findings indicated that genetic variants in m6A modification genes might be promising predictors of colorectal cancer risk.
N6-甲基腺苷（m6A）修饰在基因表达、癌症发生和转移中发挥着重要的调控作用。在此，我们旨在探讨 m6A 修饰基因中的遗传变异与结直肠癌易感性之间的关系。我们使用逻辑回归模型来研究 20 个 m6A 修饰基因中的候选单核苷酸多态性（SNP）与结直肠癌风险之间的关联。采用错误发现率（FDR）方法进行多重比较。双荧光素酶检测和 RNA m6A 定量分别用于评估转录活性和测量 m6A 水平。我们发现，SND1 rs118049207 与南京人群的结直肠癌风险显著相关（比值比（OR）=1.69，95%置信区间（95%CI）=1.31-2.18，P=6.51×10-6）。这一发现在北京人群中得到了进一步的复制（OR=1.36，95%CI=1.04-1.79，P=2.41×10-2），在联合分析中也得到了复制（OR=1.52，95%CI=1.27-1.84，P=8.75×10-6）。分层和交互分析表明，SND1 rs118049207 与患者的性别和饮酒状态相乘，增强了结直肠癌的风险（P=1.56×10-3 和 1.41×10-2）。此外，rs118049207 作为 DMRT3 驱动的 SND1 的内含子增强子。与相邻正常组织相比，结直肠肿瘤组织中 SND1 mRNA 表达明显增加。比色 m6A 定量策略表明，SND1 可以改变结直肠癌细胞系中的 m6A 水平。我们的研究结果表明，m6A 修饰基因中的遗传变异可能是结直肠癌风险的有前途的预测因子。
