Tang Rong, Zhang Yiyin, Liang Chen, Xu Jin, Meng Qingcai, Hua Jie, Liu Jiang, Zhang Bo, Yu Xianjun, Shi Si
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
PeerJ. 2020 Sep 28;8:e9602. doi: 10.7717/peerj.9602. eCollection 2020.
Pancreatic adenocarcinoma (PAAD) is among the most lethal diseases and has a dismal prognosis; however, efficient treatment is currently limited. Several studies have observed epigenetic variation during tumorigenesis, suggesting the potential role of RNA methylation, especially N6-methyladenosine (m6A) modification, as a novel epigenetic modification mediating PAAD prognosis.
The expression levels of m6A-related genes were downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA) and Genotype-Tissue Expression (GTEx) projects, and the findings were validated in four Expression Omnibus (GEO) datasets. A predictive model was constructed using a lasso regression and evaluated by a survival analysis and receiver operating characteristic curve. Consensus clustering identified two distinct subgroups with different immune activity signatures based on the expression pattern of m6A-related genes. The relationship between the mutation state of m6A-related genes and infiltration of immune cells was established and visualized using Tumor Immune Estimation Resource (https://cistrome.shinyapps.io/timer/).
Fourteen of twenty-one m6A-related genes were differentially expressed between PAAD and normal tissues in TCGA-GTEx cohort. Among these genes, and were further validated in four GEO datasets. Moreover, an m6A-based model exhibited moderate accuracy in predicting overall survival in PAAD samples. Additionally, potential m6A modification targets were screened by selecting genes from a set of 23,391 genes that not only harbored the most m6A-modified sites but also showed a robust correlation with PAAD survival. Moreover, we correlated the expression level of m6A-related genes with the immune microenvironment of pancreatic cancer for the first time. Specifically, both arm-level gain and deletion of decreased the infiltration of CD8+T cells ( < 0.05 and < 0.01, respectively).
Collectively, our findings suggest a novel anticancer strategy for restoring balanced RNA methylation in tumor cells and guide clinical physicians in developing a new practical approach for considering the impact of related genes on prognosis.
胰腺腺癌（PAAD）是最致命的疾病之一，预后很差；然而，目前有效的治疗方法有限。多项研究观察到肿瘤发生过程中的表观遗传变异，提示RNA甲基化，尤其是N6-甲基腺苷（m6A）修饰作为一种介导PAAD预后的新型表观遗传修饰的潜在作用。
从癌症基因组图谱-胰腺腺癌（TCGA）和基因型-组织表达（GTEx）项目下载m6A相关基因的表达水平，并在四个表达综合数据库（GEO）数据集中对结果进行验证。使用套索回归构建预测模型，并通过生存分析和受试者工作特征曲线进行评估。基于m6A相关基因的表达模式，共识聚类确定了具有不同免疫活性特征的两个不同亚组。利用肿瘤免疫估计资源（https://cistrome.shinyapps.io/timer/）建立并可视化m6A相关基因的突变状态与免疫细胞浸润之间的关系。
在TCGA-GTEx队列中，21个m6A相关基因中的14个在PAAD组织和正常组织之间存在差异表达。在这些基因中，和在四个GEO数据集中进一步得到验证。此外，基于m6A的模型在预测PAAD样本的总生存期方面表现出中等准确性。此外，通过从一组23391个基因中选择基因来筛选潜在的m6A修饰靶点，这些基因不仅具有最多的m6A修饰位点，而且与PAAD生存呈现出强相关性。此外，我们首次将m6A相关基因的表达水平与胰腺癌的免疫微环境相关联。具体而言，的臂水平增益和缺失均降低了CD8+T细胞的浸润（分别为<0.05和<0.01）。
总体而言，我们的研究结果提示了一种恢复肿瘤细胞中平衡RNA甲基化的新型抗癌策略，并指导临床医生制定一种新的实用方法来考虑相关基因对预后的影响。
