Exploration and validation of a novel ferroptosis-related gene signature predicting the prognosis of intrahepatic cholangiocarcinoma

Abstract

Ferroptosis plays an important role in intrahepatic cholangiocarcinoma (ICC). We aim to develop a new ferroptosis-related gene signature predicting the prognosis of ICC. We download RNA expression profiles and clinical data of ICC from TCGA and GEO databases. Ferroptosis-related differentially expressed genes (DEGs) are screened by the Wilcoxon signed-rank test. GO and KEGG enrichment analyses are performed to understand the function of DEGs and co-expressed genes. Univariate Cox and LASSO regression are used to develop a ferroptosis-related gene signature. Receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analysis were used to evaluate the prognostic value. RNA sequencing is performed in 30 patients with ICC in our medical center to validate the prognostic value of the gene signature. We identify 44 ferroptosis-related DEGs, among which four (ACSL4, IREB2, NFE2L2, and TP53) are associated with overall survival (OS). Functional enrichment analysis shows that ferroptosis-associated DEGs have an important impact on ICC carcinogenesis. A new ferroptosis-related gene signature based on DEGs is built, and the prognostic ability is confirmed by KM and ROC curves (AUC=0.777, 0.75, 0.799 for 12, 24, and 36 months, respectively). Patients with high risk scores have worse OS ( P=0.0081). In the validation cohort, the expression of DEGs is in accordance with that in the exploration cohort. The four-gene signature is also demonstrated to have a favorable prognostic value (AUC=0.69). A new predictive model based on four ferroptosis-related genes (ACSL4, IREB2, NFE2L2, and TP53) is established and shows favorable prognostic value.

Keywords

• ferroptosis
• intrahepatic cholangiocarcinoma
• prognosis
• gene signature