A Potential Fatty Acid Metabolism-Related Gene Signature for Prognosis in Clear Cell Renal Cell Carcinoma

SIMPLE SUMMARY: Clear Cell Renal Cell Carcinoma (ccRCC) is the most common and aggressive subtype of renal cancer. Abnormal fatty acid metabolism (FAM) is reported to be strongly associated with multiple malignancies, yet there is limited research in ccRCC. In this manuscript, we reported the significant role of abnormal FAM in predicting the prognosis of ccRCC. Three independent clinical cohorts (TCGA, EMTAB and our clinical cohorts with prognostic profiles and gene expression data, including RNA-seq, microarray and RT-qPCR) were applied as training and two external validation cohorts. As a result, we successfully constructed and validated a novel FAM-related gene signature (FAMGS) and nomogram for the overall survival of patients with ccRCC. Additionally, our study further elucidated the potential immune relevance and molecular mechanisms of abnormal FAM and the signature. In conclusion, the novel FAMGS constructed in this study offered a promising prognostic tool in clinic and potential therapeutic targets for ccRCC patients. ABSTRACT: This study aims to explore the role of abnormal fatty acid metabolism (FAM) in ccRCC and construct a novel fatty acid metabolism-related gene signature (FAMGS) for prognosis. Three independent ccRCC cohorts, including The Cancer Genome Atlas, E-MTAB-1980 and our clinical cohort (including RNA-seq, microarray and RT-qPCR data), were applied as training and two independent validation cohorts. Firstly, FAM levels were found to be significantly decreased in ccRCC and correlated with degrees of malignancy, confirming the pivotal role of FAM in ccRCC. Applying the least absolute shrinkage and selection operator cox regression, we established a novel FAMGS for overall survival (OS). The FAMGS divided patients into low or high-risk groups in the training cohort and were successfully validated in both the EMTAB and our clinical validation cohorts. Additionally, the FAMGS serves as an independent risk factor for OS of ccRCC. Results of the immune cell abundance identifier (ImmuCellAI) algorithm and gene set variation analysis (GSVA) revealed that patients in the high-risk group have comprehensively impaired metabolism, including lipids, amino acids and tricarboxylic acid cycle-related pathways and a more immunosuppressive tumor microenvironment. In conclusion, our study constructed and validated a novel FAMGS, which may improve the risk stratification optimization and personalized management of ccRCC.