Construction and validation of a ferroptosis-related long noncoding RNA signature in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by the accumulation of lipid-reactive oxygen species. Ferroptosis, due to the lipid peroxidation, has been reported to be strongly correlated with tumorigenesis and progression. However, the functions of the ferroptosis process in ccRCC remain unclear.

Methods: After sample cleaning, data integration, and batch effect removal, we used the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases to screen out the expression and prognostic value of ferroptosis-related lncRNAs and then performed the molecular subtyping using the K-means method. Then, the functional pathway enrichment and immune microenvironment infiltration between the different clusters were carried out. The results showed a significant difference in immune cell infiltration between the two clusters and the associated marker responded to individualized differences in treatment. Then, least absolute shrinkage and selection operator (LASSO) Cox regression was used to establish a prognostic signature based on 5 lncRNAs. This signature could accurately predicted patient prognosis and served as an independent clinical risk factor. We then combined significant clinical parameters in multivariate Cox regression and the prognostic signature to construct a clinical predictive nomogram, which provides appropriate guidance for predicting the overall survival of ccRCC patients.

Results: The prognostic differentially expressed ferroptosis-related LncRNAs (DEFRlncRNAs) were found, and 5 lncRNAs were finally used to establish the prognostic signature in the TCGA cohort, with subsequently validation in the internal and external cohorts. Moreover, we conducted the molecular subtyping and divided the patients in the TCGA cohort into two clusters showing differences in Hallmark pathways, immune infiltration, immune target expression, and drug therapies. Differences between clusters contributed to individualizing treatment. Furthermore, a nomogram was established to better predict the clinical outcomes of the ccRCC patients.

Conclusions: Our study conducted molecular subtyping and established a novel predictive signature based on the ferroptosis-related lncRNAs, which contributed to the prognostic prediction and individualizing treatment of ccRCC patients.