Construction and Validation of a Ferroptosis-Related Prognostic Signature in Kidney Renal Clear Cell Carcinoma

Abstract

Background: Kidney renal clear cell carcinoma (KIRC) is the most common and lethal renal cell carcinoma (RCC) histological subtype. Ferroptosis is a newly discovered programmed cell death and serves an essential role in tumor occurrence and development. The purpose of this study is to analyze ferroptosis-related gene (FRG) expression profiles and to construct a multi-gene signature for predicting the prognosis of KIRC patients.Methods:RNA-sequencing data and clinicopathological data of KIRC patients were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed FRGs between KIRC and normal tissues were identified using ‘limma’ package in R. GO and KEGG enrichment analyses were conducted to elucidate the biological functions and pathways of differentially expressed FRGs. Consensus clustering was used to investigate the relationship between the expression of FRGs and clinical phenotypes. Univariate and the least absolute shrinkage and selection operator (LASSO) Cox regression analysis were used to screen genes related to prognosis and construct the optimal signature. Then, a nomogram was established to predict individual survival probability by combining clinical features and prognostic signature.Results: A total of 19 differentially expressed FRGs were identified. Consensus clustering identified two clusters of KIRC patients with distinguished prognostic. Functional analysis revealed that metabolism-related pathways were enriched, especially lipid metabolism. A 7-gene ferroptosis-related prognostic signature was constructed to stratify the TCGA training cohort into high- and low-risk groups where the prognosis was significantly worse in the high-risk group. The signature was identified as an independent prognostic indicator for KIRC. These findings were validated in the testing cohort, the entire cohort, and the International Cancer Genome Consortium (ICGC) cohort. We further demonstrated that the signature-based risk score was highly associated with the KIRC progression. Further stratified survival analysis showed that the high-risk group had a significantly lower overall survival (OS) rate than those in the low-risk group. Moreover, we constructed a nomogram that had a strong ability to forecast the OS of the KIRC patients.Conclusion: We constructed a ferroptosis-related prognostic signature, which might provide a reliable prognosis assessment tool for clinician to guide clinical decision-making and outcomes research.

A Novel Ferroptosis-Related Gene Signature Robustly Predicts Clinical Prognosis And Tumor Immunity in Patients With Kidney Renal Clear Cell Carcinoma

“…In cancer cells, GLS2 upregulation can induce an antiproliferative response with cell cycle arrest (47). Notably, high expression of risk genes, such as CD44, FANCD2 and CHAC1 as well as low expression of NCOA4 were found to be correlated with worse OS in KIRC (21,22), in line with our results. Taken together, these genes may be involved in KIRC via involved in ferroptosis.…”

“…Ferroptosis-related genes such as BRCA1-associated protein 1 (BAP1) (17), nuclear factor erythroid 2-related factor 2 (NRF2) (18,19), and glutathione peroxidase 4 (GPX4) (20) are found to be implicated in tumorigenesis and progression. Although recent studies have revealed that some ferroptosis-related genes, such as Cystathionine beta-synthase (CBS), CD44, Fanconi anemia complementation group D2 (FANCD2), glutamate exchanger xCT (SLC7A11) are associated with high-risk patients with KIRC (21,22), the key ferroptosis-related genes that could predict clinical prognosis and tumor immunity in KIRC have not been fully discovered.…”