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 the kidney is an iron metabolism-related organ, exploring and assessing the clinical value of ferroptosis, an iron-dependent regulated cell death, is practical and important. Methods Prognostic ferroptosis-related differentially expressed genes (DEGs) were identified from the KIRC cohort in the cancer genome atlas (TCGA) database, from which a prognostic signature was established using Lasso-penalized Cox regression analysis. Each patient in the KIRC cohort and the E-MTAB-1980 cohort (from the ArrayExpress database) was assigned a calculated signature-correlated risk score and categorized to be either in the 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 based on overall survival (OS) in both cohorts. Finally, risk-related DEGs were identified in both cohorts and subjected to enrichment analyses for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and immune infiltration. Results Among 60 ferroptosis-related genes, 32 prognostic DEGs were identified, from which we constructed a prognostic 12-gene signature with CARS1, HMGCR, CHAC1, GOT1, CD44, STEAP3, AKR1C1, CBS, DPP4, FANCD2, SLC1A5 and NCOA4. Patients in both cohorts were divided into high- and low-risk groups, which were visually distributed in two sets and had positive-risk-related mortality. The K-M survival and the ROC curves validated that the signature has prognostic value 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 terms in GO and KEGG not only showed a high iron correlation but also, interestingly, immune relevance of 3 immune cells (macrophages, mast cells and regulatory T cells) and 1 immune-related function (antigen processing cell co-stimulation). Conclusion We established a novel 12 ferroptosis-related-gene signature that was proven to be an independent prognostic predictor for OS and inferred to be related to tumour immunity in ccRCC; however, the underlying mechanism is still poorly characterized and needs further exploration.

Identification and Validation of a Ferroptosis-Related Long Non-Coding RNA (FRlncRNA) Signature to Predict Survival Outcomes and the Immune Microenvironment in Patients With Clear Cell Renal Cell Carcinoma

“…In addition, ICGC cohorts were used to evaluate the constructed model, which showed a good ability to predict the survival rate of patients with ccRCC (Supplementary Figure 2A-E). These results showed that the FRlncRNA signature can be a good indicator in predicting the prognosis of patients compared with other existing signatures reported in recent studies (Supplementary Table S2) (Canxuan and Dan, 2021;Hong et al, 2021;Ma et al, 2021;Xing et al, 2021;Yu et al, 2021;Zheng et al, 2021). Taken together, our data implied that the FRlncRNA signature showed a stable prognostic-predictive ability.…”

“…Through linear correlation analysis (R > 0.3 and p < 0.001) and literature retrieval ( Shao et al, 2019 ; Xiong et al, 2021a ; Hong et al, 2021 ), we selected three target genes (BNIP3, RRM2, and GOT1) for further verification. BNIP3 ( p < 0.05) and RRM2 ( p < 0.05) were significantly upregulated in ccRCC tissues, but GOT1 ( p < 0.05) was significantly downregulated in ccRCC tissues ( Figures 11A–C ).…”

Upregulation of Ferroptosis-Related Fanconi Anemia Group D2 is a Poor Prognostic Factor and Indicator of Tumor Immune Cell Infiltration in Lung Adenocarcinoma

“…Moreover, FANCD2 plays an immunosuppressive role by downregulating immunostimulators, such asIL6R, TMEM173, TNFSF13, CD40LG, and HHLA2. Therefore, the results implied that FANCD2 contributes to tumor immune escape by modulating the immunosuppressive microenvironment, which was consistent with previous studies [35,36].…”

Identification and Validation of a Ferroptosis-Related Signature for Predicting Prognosis and Immune Microenvironment in Papillary Renal Cell Carcinoma

“…Recent study indicated that 11-genes ferroptosis-related signature accurately predicts clinical prognosis in patients with CCRCC. 23 Intriguingly, these 4-genes ferroptosis-related signatures are specific for PRCC patients compared with the discovered ferroptosis-related signature in CCRCC, 23 , 24 which is benefit to develop specific clinical drugs and diagnostic strategies for PRCC patients only.…”