Construction of A Novel Ferroptosis-related Prognostic Risk Signature for Survival Prediction in Clear Cell Renal Cell Carcinoma Patients
Urology Journal,
Vol. 19 No. 04 (2022),
11 Shahrivar 2022
,
Page 289-299
https://doi.org/10.22037/uj.v19i04.6999
Abstract
Purpose: Targeted ferroptosis is a reliable therapy to inhibit tumor growth and enhance immunotherapy. This study generated a novel prognostic risk signature based on ferroptosis-related genes (FRGs), and explored the ability in clinic for clear cell renal cell carcinoma (ccRCC).
Materials and Methods: The expression profile of mRNA and FRGs for ccRCC patients were exacted from The Cancer Genome Atlas (TCGA) database. A ferroptosis-related prognostic risk signature was constructed based on univariable and multivariable Cox-regression analysis. Kaplan-Meier (KM) survival curves and receiver operating characteristic (ROC) curves were performed to access prognostic value of riskscore. A nomogram integrating riskscore and clinical features was established to predict overall survival (OS). Based on differentially expressed genes between high- and low-OS groups with 5-year OS, function enrichment analyses and single-sample gene set enrichment analysis (ssGSEA) were investigated to immune status.
Results: A 9-FRGs prognostic risk signature was constructed based on 37 differentially expressed FRGs. ROC and KM curves showed that riskscore has excellent reliability and predictive ability; Cox regression disclosed the riskscore as an independent prognosis for ccRCC patients. Then, the C-index and calibration curve demonstrated the good performance of nomogram in training and validation cohort, and its predictive ability better than other features. Immune-related biological processes were enriched by function enrichment analysis, and the immune-related cells and functions were differential by ssGSEA between high- and low-OS groups.
Conclusion: Our study identified and verified a novel 9-FRGs prognostic signature and nomogram to predict OS, providing a novel sight to explore targeted therapy of ferroptosis for ccRCC.
- Clear cell renal cell carcinoma, ferroptosis, risk signature, immune, prognosis
How to Cite
References
Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017;3:17009.
Capitanio U, Bensalah K, Bex A, et al. Epidemiology of Renal Cell Carcinoma. Eur Urol. 2019;75:74-84.
Vuong L, Kotecha RR, Voss MH, Hakimi AA. Tumor Microenvironment Dynamics in Clear-Cell Renal Cell Carcinoma. Cancer Discov. 2019;9:1349-57.
Majer W, Kluzek K, Bluyssen H, Wesoly J. Potential Approaches and Recent Advances in Biomarker Discovery in Clear-Cell Renal Cell Carcinoma. J Cancer. 2015;6:1105-13.
Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171:273-85.
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060-72.
Gao M, Yi J, Zhu J, et al. Role of Mitochondria in Ferroptosis. Mol Cell. 2019;73:354-63 e3.
Lippmann J, Petri K, Fulda S, Liese J. Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma. Transl Oncol. 2020;13:100785.
Xu T, Ding W, Ji X, et al. Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med. 2019;23:4900-12.
Miess H, Dankworth B, Gouw AM, et al. The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene. 2018;37:5435-50.
Zhou N, Bao J. FerrDb: a manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations. Database (Oxford). 2020;2020.
Hsieh JJ, Le VH, Oyama T, et al. Chromosome 3p Loss-Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;36:Jco2018792549.
Jonasch E, Gao J, Rathmell WK. Renal cell carcinoma. BMJ. 2014;349:g4797.
Wu G, Wang Q, Xu Y, Li Q, Cheng L. A new survival model based on ferroptosis-related genes for prognostic prediction in clear cell renal cell carcinoma. Aging. 2020;12:14933-48.
Bai D, Feng H, Yang J, et al. Genomic analysis uncovers prognostic and immunogenic characteristics of ferroptosis for clear cell renal cell carcinoma. Molecular Therapy - Nucleic Acids. 2021.
Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57-62.
Lin W, Wang C, Liu G, et al. SLC7A11/xCT in cancer: biological functions and therapeutic implications. Am J Cancer Res. 2020;10:3106-26.
Chen D, Tavana O, Chu B, et al. NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression. Mol Cell. 2017;68:224-32 e4.
Feng C, Sun Y, Ding G, et al. PI3Kbeta inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways. Sci Rep. 2015;5:9465.
Si M, Lang J. The roles of metallothioneins in carcinogenesis. J Hematol Oncol. 2018;11:107.
Sun X, Niu X, Chen R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology. 2016;64:488-500.
Li Z, Jiang L, Chew SH, et al. Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia. Redox Biol. 2019;26:101297.
Bui MH, Seligson D, Han KR, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res. 2003;9:802-11.
Efimova I, Catanzaro E, Van der Meeren L, et al. Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity. J Immunother Cancer. 2020;8.
Kloditz K, Fadeel B. Three cell deaths and a funeral: macrophage clearance of cells undergoing distinct modes of cell death. Cell Death Discov. 2019;5:65.
Braun DA, Hou Y, Bakouny Z, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26:909-18.
Wang W, Green M, Choi JE, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270-4.
Ma X, Xiao L, Liu L, et al. CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability. Cell Metab. 2021;33:1001-12.e5.
Matsushita M, Freigang S, Schneider C, et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med. 2015;212:555-68.
Zou Y, Palte MJ, Deik AA, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. 2019;10:1617.
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