Identification and validation of a ferroptosis-related signature for prediction of the prognosis and tumor microenvironment in patients with chromophobe renal cell carcinoma.

Background: Ferroptosis is a novel form of regulated cell death that is different from other forms, which has an important role in tumor growth inhibition. The purpose of this study was to construct and validate a prognostic signature related to ferroptosis in chromophobe renal cell carcinoma (ChRCC) and to explore its role in immune cell infiltration and systemic therapy.

Methods: The gene expression profiles of ChRCC patients obtained from The Cancer Genome Atlas (TCGA) database were used to identify differentially expressed prognostic ferroptosis-related genes (FRGs) by univariate Cox proportional hazards analyses. Ferroptosis molecular subtypes were obtained by consensus clustering analysis. The FRG-based signature in the training set was established by least absolute shrinkage and selection operator analysis and verified in the testing set. The association between molecular subtypes and the prognostic signature and immune microenvironment was explored to predict responses to immunotherapy. Immunohistochemistry was used to verify expression of the FRG-based signature externally.

Results: ChRCC patients were divided into two FRG subtypes. Two FRGs (TFRC and SLC7A11) were identified to construct the prognostic signature. The high-risk group and cluster 2 had worse overall survival than the low-risk group and cluster 1, respectively. The low-risk group and cluster 1 had higher levels of immune cell infiltration and expression of MHC and immune checkpoint molecules than the high-risk group and cluster 2. The risk score was a predictor of overall survival and had a good predictive ability, which was verified in the testing set and evaluated by ROC and calibration curves. The high-risk group had a higher tumor mutation burden. The different sensitivities of targeted drugs in patients with different risks were evaluated. External immunohistochemical analysis showed that TFRC and SLC7A11 were highly expressed in tumor tissues compared with para-cancer normal tissues, and the expression level was significantly associated with a more advanced stage and worse cancer-specific survival.

Conclusions: An FRG signature was identified and validated to predict the clinicopathological features and prognosis of ChRCC. A significant association between the signature and immune cell infiltration, immune checkpoint expression, and drug response is helpful to guide comprehensive treatment of ChRCC.