Abstract
Kidney renal clear cell carcinoma (KIRC) is one of the most prevalent primary malignancies with high heterogeneity in the urological system. Growing evidence implies that lactate is a significant carbon source for cell metabolism and plays a vital role in tumor development, maintenance, and therapeutic response. However, the global influence of lactate-related genes (LRGs) on prognostic significance, tumor microenvironment characteristics, and therapeutic response has not been comprehensively elucidated in patients with KIRC. In the present study, we collected RNA sequencing and clinical data of KIRC from The Cancer Genome Atlas (TCGA), E-MTAB-1980, and GSE22541 cohorts. Unsupervised clustering of 17 differentially expressed LRG profiles divided the samples into three clusters with distinct immune characteristics. Three genes (FBP1, HADH, and TYMP) were then identified to construct a lactate-related prognostic signature (LRPS) using the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. The novel signature exhibited excellent robustness and predictive ability for the overall survival of patients. In addition, the constructed nomogram based on the LRPS-based risk scores and clinical factors (age, gender, tumor grade, and stage) showed a robust predictive performance. Furthermore, patients classified by risk scores had distinguishable immune status, tumor mutation burden, response to immunotherapy, and sensitivity to drugs. In conclusion, we developed an LRPS for KIRC that was closely related to the immune landscape and therapeutic response. This LRPS may guide clinicians to make more precise and personalized treatment decisions for KIRC patients.
Highlights
Renal cell carcinoma (RCC) represents one of the most common primary malignancies with increasing incidence in the urological system, constituting 2%–3% of adult malignant tumors [1]
Despite the increasing incidence of Kidney renal clear cell carcinoma (KIRC), the survival of patients with advanced RCC has been markedly improved with molecular target–drug combinations combined and Immune checkpoint blockade (ICB)
We identified 17 differentially expressed lactate-related genes (LRGs), three of which were determined to construct an lactate-related prognostic signature (LRPS) using least absolute shrinkage and selection operator (LASSO) and Cox regression analyses
Summary
Renal cell carcinoma (RCC) represents one of the most common primary malignancies with increasing incidence in the urological system, constituting 2%–3% of adult malignant tumors [1]. Intervening metabolic pathways are attractive therapeutic targets with prognostic value for patients with cancers [13]. In this regard, LDHA converts pyruvate into lactate and NAD+, as well as features in the metabolism of tumor cells by targeting c-Myc and hypoxia-inducible factor-1 (HIF-1), and is considered as a promising anticancer target [6]. MCT inhibitors such as AZD3965, AR-C155858, and a-cyano-4hydroxycinnamate (CHC) reduce the levels of lactate in tumor cells via the inhibition of SLC16A1 and SLC16A7 [16, 17] Of these inhibitors, AZD3965 acquired encouraging preclinical success for advanced cancer in a phase I clinical trial [18]. Targeting lactate metabolism has been regarded as an exciting strategy for cancer therapy
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