N6-甲基腺嘌呤（m6A）修饰已被证明在结直肠癌（CRC）患者的预后效果中发挥至关重要的作用。然而，m6A在生存率和免疫治疗反应中的潜在机制仍不清楚。在这里，我们研究了与m6A调节因子相关的基因，并开发了一个风险评分来预测CRC患者的整体生存期（OS）。我们从癌症基因组图谱（TCGA）数据库中获取了COAD / READ样本的RNA-seq转录组谱数据。我们进行了绝对收缩和选择操作（LASSO）- Cox回归分析，以确定与m6A相关的基因表达签名，并将所选基因输入逐步回归以在TCGA中开发预后风险评分，并进一步验证其在基因表达的广义数据库（GEO）数据集中对CRC生存的预测性能。根据我们的结果，在TCGA和GEO数据集中，包含18个m6A相关mRNA的风险评分与CRC生存显著相关。分层分析还证实，不同年龄、性别、T期和肿瘤、淋巴结、转移（TNM）分期的高风险评分都是不良因素。与临床特征相结合的m6A相关预后评分产生了时间依赖性的接收者操作特征曲线下面积（AUC），在TCGA队列中预测了1、3、5年的CRC OS的AUC分别为0.85（95％CI：0.79-0.91）、0.84（95％CI：0.79-0.90）和0.80（95％CI：0.71-0.88）。此外，高风险组的肿瘤基因突变更为频繁，肿瘤微环境中免疫细胞的组成在低风险组和高风险组之间显著不同。低风险组的微卫星不稳定性（MSI）评分、T细胞排斥评分和功能失调评分较低，这表明低风险患者可能比高风险患者对免疫治疗有更好的反应。总之，从m6A相关基因表达标志物中得出的预后风险评分可作为潜在的CRC生存预测因子和预测CRC患者免疫治疗反应的指标。版权所有©2023年于，王，孙，周，胡，胡，何，林，陈，徐，邓洛普，西奥多拉图，丁和李。

N6-methyladenosine (m6A) modification has been demonstrated to exhibit a crucial prognostic effect on colorectal cancer (CRC). Nonetheless, potential mechanism of m6A in survival rate and immunotherapeutic response remains unknown. Here we investigated the genes associated with m6A regulators and developed a risk score for predicting the overall survival (OS) of CRC patients. RNA-seq transcriptomic profiling data of COAD/READ samples were obtained from The Cancer Genome Atlas (TCGA) database. Absolute Shrinkage and Selection Operator (LASSO)- Cox regression analysis was conducted to identify the m6A-related gene expression signatures and the selected genes were inputted into stepwise regression to develop a prognostic risk score in TCGA, and its predictive performance of CRC survival was further validated in Gene Expression Omnibus (GEO) datasets. According to our results, the risk score comprising 18 m6A-related mRNAs was significantly associated with CRC survival in both TCGA and GEO datasets. And the stratified analysis also confirmed that high-risk score acted as a poor factor in different age, sex, T stage, and tumour, node, metastasis (TNM) stages. The m6A-related prognostic score in combination with clinical characteristics yielded time-dependent area under the receiver operating characteristic curve (AUCs) of 0.85 (95%CI: 0.79-0.91), 0.84 (95%CI: 0.79-0.90) and 0.80 (95%CI: 0.71-0.88) for the prediction of the 1-, 3-, 5-year OS of CRC in TCGA cohort. Furthermore, mutation of oncogenes occurred more frequently in the high-risk group and the composition of immune cells in tumour microenvironment (TME) was significantly distinct between the low- and high-risk groups. The low-risk group had a lower microsatellite instability (MSI) score, T-cell exclusion score and dysfunction score, implying that low-risk patients may have a better immunotherapy response than high-risk patients. In summary, a prognostic risk score derived from m6A-related gene expression signatures could serve as a potential prognostic predictor for CRC survival and indicator for predicting immunotherapy response in CRC patients.Copyright © 2023 Yu, Wang, Sun, Zhou, Hu, Hu, He, Lin, Chen, Xu, Dunlop, Theodoratou, Ding and Li.