Although new diagnostic techniques and treatments are increasingly updated, the clinical outcomes of CRC patients are still not encouraging with a low survival rate. N6-methyladenosine as a popular modification on mRNA is associated with multiple types of cancers. Our purpose is to evaluate gene signature and prognostic ability of N6-methyladenosine in CRC. We used the gene expression, copy number variation, simple nucleotide variation and clinical messages from The Cancer Genome Atlas database. We first identified mutation and copy number variations of N6-methyladenosine regulatory genes in both colon adenocarcinoma and rectum adenocarcinoma. Fourteen of all 17 N6-methyladenosine regulatory genes were related with higher mRNA expression, whereas deletion leads to reduced expression. Using univariate Cox regression analysis, RBM15, YTHDC2, and METTL14 genes in the rectum adenocarcinoma samples were conspicuously associated with the prognosis of patients. Based on the least absolute shrinkage and selection operator regression models, we built a 2-gene (YTHDC2 and IGF2BP3) signature of N6-methyladenosine regulators with prognostic ability. The 1-, 3-, and 5-year AUCs of this signature were all greater than 0.6, and the P-value for risk prediction for patients was also less than 0.0001. Moreover, high IGF2BP3 gene expression was significantly associated with IFN-γ in colon adenocarcinoma , and related to the azurophil granule membrane pathway in rectum adenocarcinoma. High YTHDC2 expression in colon adenocarcinoma is closely related to cell energy metabolism. In the rectum adenocarcinoma, high YTHDC2 gene expression is related to the cell centrosome pathway. In conclusion, for the first time, we identified genetic changes of N6-methyladenosine modulators and built a prognostic gene signature in CRC.

Impact statement

Although new diagnostic techniques and treatments are increasingly updated for CRC, the clinical outcomes of CRC patients are still not encouraging with a low survival rate. N6-methyladenosine (m6A) as a popular modification on mRNA is associated with multiple types of cancers. Our purpose is to identify gene signature and prognostic ability of m6A modulators in CRC. For the first time, we identified genetic changes of m6A modulators and built prognostic gene signature in CRC, which may provide effective targets for the diagnosis and management of CRC.

中文翻译：

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M6a 调节因子在结直肠癌中的基因特征和预后价值。

尽管新的诊断技术和治疗方法不断更新，但结直肠癌患者的临床结果仍然不乐观，存活率低。N6-甲基腺苷作为一种流行的 mRNA 修饰与多种类型的癌症有关。我们的目的是评估 N6-甲基腺苷在 CRC 中的基因特征和预后能力。我们使用了来自癌症基因组图谱数据库的基因表达、拷贝数变异、简单核苷酸变异和临床信息。我们首先在结肠腺癌和直肠腺癌中鉴定了 N6-甲基腺苷调节基因的突变和拷贝数变异。所有 17 个 N6-甲基腺苷调节基因中有 14 个与较高的 mRNA 表达相关，而缺失导致表达降低。使用单变量 Cox 回归分析、RBM15、YTHDC2、直肠腺癌样本中的 METTL14 和 METTL14 基因与患者的预后显着相关。基于最小绝对收缩和选择算子回归模型，我们构建了具有预后能力的 N6-甲基腺苷调节因子的 2 基因（YTHDC2 和 IGF2BP3）特征。该签名的 1 年、3 年和 5 年 AUC 均大于 0.6，并且患者风险预测的P值也小于 0.0001。此外，高 IGF2BP3 基因表达与结肠腺癌中的 IFN-γ 显着相关，并与直肠腺癌中的天蓝色颗粒膜通路相关。结肠腺癌中YTHDC2的高表达与细胞能量代谢密切相关。在直肠腺癌中，YTHDC2基因的高表达与细胞中心体通路有关。总之，我们首次确定了 N6-甲基腺苷调节剂的遗传变化，并在 CRC 中建立了预后基因特征。

影响陈述

尽管针对 CRC 的新诊断技术和治疗方法不断更新，但 CRC 患者的临床结果仍然不乐观，存活率较低。N6-甲基腺苷 (m6A) 作为一种流行的 mRNA 修饰与多种类型的癌症有关。我们的目的是确定 m6A 调节剂在 CRC 中的基因特征和预后能力。我们首次在 CRC 中鉴定了 m6A 调节剂的遗传变化并构建了预后基因特征，这可能为 CRC 的诊断和管理提供有效的靶点。