Yun Duo, Yang Zhirong, Zhang Shuman, Yang Hai, Liu Dongxue, Grützmann Robert, Pilarsky Christian, Britzen-Laurent Nathalie
Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Front Cell Dev Biol. 2022 Aug 19;10:975684. doi: 10.3389/fcell.2022.975684. eCollection 2022.
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（PDAC）是最具侵袭性的消化系统恶性肿瘤，因其常出现晚期诊断、进展迅速且对治疗耐药。随着全球PDAC发病率的上升，迫切需要新的预后生物标志物和治疗靶点。最近，RNA甲基化已成为不同癌症中的一种新的致癌机制。5-甲基胞嘧啶（m5C）是最常见的RNA修饰之一，存在于包括mRNA在内的多种RNA种类上，从而调节基因表达。在此，我们研究了m5C调节因子相关转录特征在PDAC中的预后作用。我们从公开可用的数据集中评估了239个PDAC样本中的m5C调节因子状态和表达。我们使用无监督一致性聚类分析根据m5C调节因子表达对PDAC进行分类。从差异表达基因（DEG）的结果特征中，我们选择与预后相关的DEG来对患者进行分层，并通过LASSO和多变量Cox回归分析构建一个评分特征（m5C评分）。m5C评分代表了一个高度显著的独立预后标志物。高m5C评分与不同PDAC队列中的不良预后相关，并与鳞状/基底亚型以及包括Ras、MAPK和PI3K途径在内的激活的癌症相关途径有关。此外，m5C评分与对PARP、EGFR、AKT、HER2和mTOR的途径特异性抑制剂的敏感性相关。高m5C评分的肿瘤具有整体免疫排斥、低CD8 T细胞浸润和较高的PD-L1表达的特征。总体而言，m5C评分代表了PDAC预后和治疗反应的有力预测指标，与不良分子亚型和免疫微环境相关。
