Identification and Validation of Constructing the Prognostic Model With Four DNA Methylation-Driven Genes in Pancreatic Cancer

Guangyu Chen,Yupei Zhao,Junyu Long,Jinxin Tao,Fangyu Zhao,Jiangdong Qiu,Gang Yang,Taiping Zhang,Yuezhe Liu,Ruizhe Zhu

doi:10.3389/fcell.2021.709669

Abstract

Background: Pancreatic cancer (PC) is a highly aggressive gastrointestinal tumor and has a poor prognosis. Evaluating the prognosis validly is urgent for PC patients. In this study, we utilized the RNA-sequencing (RNA-seq) profiles and DNA methylation expression data comprehensively to develop and validate a prognostic signature in patients with PC. Methods: The integrated analysis of RNA-seq, DNA methylation expression profiles, and relevant clinical information was performed to select four DNA methylation-driven genes. Then, a prognostic signature was established by the univariate, multivariate Cox, and least absolute shrinkage and selection operator (LASSO) regression analyses in The Cancer Genome Atlas (TCGA) dataset. GSE62452 cohort was utilized for external validation. Finally, a nomogram model was set up and evaluated by calibration curves. Results: Nine DNA methylation-driven genes that were related to overall survival (OS) were identified. After multivariate Cox and LASSO regression analyses, four of these genes (RIC3, MBOAT2, SEZ6L, and OAS2) were selected to establish the predictive signature. The PC patients were stratified into two groups according to the median risk score, of which the low-risk group displayed a prominently favorable OS compared with the high-risk group, whether in the training (p < 0.001) or validation (p < 0.01) cohort. Then, the univariate and multivariate Cox regression analyses showed that age, grade, risk score, and the number of positive lymph nodes were significantly associated with OS in PC patients. Therefore, we used these clinical variables to construct a nomogram; and its performance in predicting the 1-, 2-, and 3-year OS of patients with PC was assessed via calibration curves. Conclusion: A prognostic risk score signature was built with the four alternative DNA methylation-driven genes. Furthermore, in combination with the risk score, age, grade, and the number of positive lymph nodes, a nomogram was established for conveniently predicting the individualized prognosis of PC patients.

Highlights

Pancreatic cancer (PC) is a lethal solid tumor with a poor prognosis
After the filtration with cutoff value (|logFC| > 1, false discovery rate (FDR) < 0.01), 8,809 differentially expressed genes (DEGs) were screened for further analysis, including 5,221 upregulated DEGs and 3,588 downregulated DEGs (Supplementary Table S1)
We used p-value < 0.05 to identify the differentially methylation expressed genes, a correlation

Summary

Introduction

Pancreatic cancer (PC) is a lethal solid tumor with a poor prognosis. The amount of estimated new PC cases and deaths both stand in second place in gastrointestinal cancer in the United States (Siegel et al, 2020). Surgery remains the foundation of curing PC, but the majority (80%–85%) of PC patients who present with unresectable or metastatic tumors lose the chance of surgery (Mizrahi et al, 2020) Whether it is early detection of resectable PC or late diagnosis of unresectable and metastatic PC, a wide range of PC patients require routine chemotherapy including 5fluorouracil (5-FU)/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine with nabpaclitaxel and other multidrug regimens (Conroy et al, 2011; Von Hoff et al, 2013). We utilized the RNA-sequencing (RNA-seq) profiles and DNA methylation expression data comprehensively to develop and validate a prognostic signature in patients with PC

Methods

Results

Conclusion