DataSheet1_An m5C methylation regulator-associated signature predicts prognosis and therapy response in pancreatic cancer.PDF

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive digestive malignancy due to frequent late-stage diagnosis, rapid progression and resistance to therapy. With increasing PDAC incidence worldwide, there is an urgent need for new prognostic biomarkers and therapy targets. Recently, RNA methylation has emerged as a new tumorigenic mechanism in different cancers. 5-methylcytosine (m5C) is one of the most frequent RNA modifications and occurs on a variety of RNA species including mRNA, thereby regulating gene expression. Here we investigated the prognostic role of m5C-regulator-associated transcriptional signature in PDAC. We evaluated m5C-regulator status and expression in 239 PDAC samples from publicly available datasets. We used unsupervised consensus clustering analyses to classify PDACs based on m5C-regulator expression. From the resulting signature of differentially expressed genes (DEGs), we selected prognosis-relevant DEGs to stratify patients and build a scoring signature (m5C-score) through LASSO and multivariate Cox regression analyses. The m5C-score represented a highly significant independent prognostic marker. A high m5C-score correlated with poor prognosis in different PDAC cohorts, and was associated with the squamous/basal subtype as well as activated cancer-related pathways including Ras, MAPK and PI3K pathways. Furthermore, the m5C-score correlated with sensitivity to pathway-specific inhibitors of PARP, EGFR, AKT, HER2 and mTOR. Tumors with high m5C-score were characterized by overall immune exclusion, low CD8+ T-cell infiltration, and higher PD-L1 expression. Overall, the m5C-score represented a robust predictor of prognosis and therapy response in PDAC, which was associated with unfavorable molecular subtypes and immune microenvironment.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是最具侵袭性的消化系恶性肿瘤，因其确诊时多已处于晚期、进展迅速且对治疗产生耐药性。随着全球范围内PDAC发病率持续攀升，亟需开发新型预后生物标志物与治疗靶点。近年来，RNA甲基化已被证实是多种癌症的新型致癌机制。5-甲基胞嘧啶（5-methylcytosine, m5C）是最为常见的RNA修饰类型之一，可发生于包括信使RNA（mRNA）在内的多种RNA分子，进而调控基因表达。本研究旨在探讨m5C调控因子相关转录特征在PDAC中的预后价值。我们从公开数据集获取239例PDAC样本，对其中m5C调控因子的状态与表达水平进行了分析。基于m5C调控因子的表达谱，采用无监督共识聚类分析对PDAC样本进行分型。从筛选得到的差异表达基因（differentially expressed genes, DEGs）特征集中，我们选取与预后相关的DEGs，通过LASSO与多因素Cox回归分析，构建了用于患者风险分层的评分特征（m5C-score）。m5C-score是一项具有显著统计学意义的独立预后标志物。在多组PDAC队列中，高m5C-score与不良预后显著相关，同时与鳞状/基底样亚型以及Ras、MAPK、PI3K等激活的癌症相关通路密切关联。此外，m5C-score与PARP、EGFR、AKT、HER2及mTOR等通路特异性抑制剂的治疗敏感性相关。高m5C-score的肿瘤整体呈现免疫排斥表型，CD8+ T细胞浸润水平较低，且PD-L1表达水平更高。综上，m5C-score可作为PDAC患者预后与治疗响应的可靠预测指标，其与不良分子亚型及免疫微环境特征密切相关。