A novel ferroptosis-related 12-gene signature predicts clinical prognosis and reveals immune relevancy in clear cell renal cell carcinoma

Abstract

Background Clear cell renal cell carcinoma (ccRCC) is still highly aggressive and lethal even with various therapeutic approaches. As kidney is an iron-metabolism-related organ, exploring and assessing the clinical value of ferroptosis, an iron-dependent regulated cell death, is practical and significant. Methods Prognostic ferroptosis-related differentially expressed genes (DEGs) were identified from KIRC cohort in TCGA database, from which a prognostic signature was established using the Lasso-penalized Cox regression analysis. Each patient in the KIRC cohort and the E-MTAB-1980 cohort (from the ArrayExpress database) was assigned with a calculated signature-correlated risk score and categorized to be either in high- or low-risk group divided by the median risk score in the KIRC cohort. Then, the independent prognostic value of the signature was further assessed by Kaplan-Meier (K-M) survival, time-dependent receiver operating characteristic (ROC) and Cox regression analyses base on overall survival (OS) in both cohorts. Lastly, risk-related DEGs were identified in both cohorts and applied with the enrichment analyses for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and immune infiltration. Results Within 60 ferroptosis-related genes, 32 prognostic DEGs were identified, from which we constructed a prognostic 12-gene signature including CARS1, HMGCR, CHAC1, GOT1, CD44, STEAP3, AKR1C1, CBS, DPP4, FANCD2, SLC1A5 and NCOA4. Patients in both cohorts were divided into high- and low-risk group which were visually distributed in two sets and with positive-risk-related mortality. The K-M survival and the ROC curves validated the signature as prognostic valuable with P <0.05 and area under the curve >0.7 in both cohorts, respectively. Multivariate Cox regression further confirmed the risk score as an independent prognostic predictor for OS. Commonly enriched term in GO and KEGG not only shown a highly iron correlation, but also, interesting, an immunity relevancy of 3 immune cells (macrophages, mast cells and regulatory T cell) and 1 immune-related function (antigen processing cell co-stimulation). Conclusion We established a novel 12 ferroptosis-related-gene signature which was proved as an independent prognostic predictor for OS and inferred as relating to tumor immunity in ccRCC, however, the underlying mechanism is still poorly characterized and needed further exploration.

Identification of Anoikis-Related Prognostic Genes and Construction of a Prognostic Model for Hepatocellular Carcinoma Based on Single-Cell and Bulk Transcriptomic Analysis

“…A higher C-index value suggests better predictive performance of the model. Furthermore, we compared the C-index of AnoRGs with previously published prognostic models related to anoikis-related genes [21][22][23][24][25][26][27] . Our results showed that the C-index of our model was the highest (Fig.…”