Prognostic Utility of TFCP2‐Mediated Genes in Clear Cell Renal Cell Carcinoma Inflammation and Outcome

Abstract

Introduction and ObjectiveThe alpha globin transcription factor CP2 (TFCP2) encoded by the TFCP2 gene has been implicated in either tumor suppression or pro‐oncogenic tendencies depending on the cancer. TCFP2 has also been linked to inflammatory milieu in various diseases, making it and its regulatory targets possible prognostic markers for inflammation infiltrate levels as well as survival. This study explores the relationship between survival and predicted inflammatory features of clear cell renal cell carcinoma (ccRCC) and TFCP2‐mediated gene expression.MethodsGenes which contained at least one binding site for TCFP2 in their promoter region based on ChIP‐seq data were obtained from the MSig database, and 60 genes were analyzed (including TCFP2). Kaplan‐Meier plots of overall survival in ccRCC cases in relation to TCFP2 and TCFP2‐regulated gene expression levels were generated using TCGA data, with the R2 platform “KaplanScan” algorithm creating a “high” and “low” expression cohorts (n=267,266). A step‐down Bonferroni method for multiple hypothesis correction set a significance cutoff of p<0.0033. The TIMER 2.0 platform was used to estimate immune infiltration (CD4/8+ T cells, Neutrophils, B cells, and NK cells) correlation with genes shown to be significant in terms of survival.ResultsFrom the original 60 TCFP2 and TCFP2‐mediated genes, 18 showed significant association with overall survival outcome following correction (p<0.0033), with analysis showing increased expression associated with both better (10 genes) and worse outcomes (8 genes). Immune infiltration was correlated with many of those genes, particularly in regards to CD4+ T cell and neutrophils. Weak positive correlation between CD4+ T cell infiltration and expression (r>0.30, p<0.01) was observed in 9 out of 18 genes, with one gene (EIF4G2) showing a moderate (r>0.50, p<0.001) positive correlation of r=0.554. Regarding neutrophil infiltration, 7 genes showed weak positive correlation while one gene (CDC42SE1) showed strong (r>0.70, p<0.001) positive correlation (r=0.716). For NK cells, we a saw weak negative correlation in 6 genes (‐r>|‐0.30|, p<0.01). Findings for other cells weren't significant. While TCFP2 expression itself did not show a significant association with survival, it did show a weak positive correlation with both CD4+ T cell and neutrophil infiltration and a weak negative correlation with NK levels.ConclusionsSignificant survival differences in the ccRCC cases were observed based on 18 different TCFP2‐regulated gene expression levels, suggesting prognostic utility. TCFP2 expression itself was not associated with a given prognosis, and further protein‐based studies may be useful to determine if this result is due to post‐transcriptional modification unaccounted for in this mRNA study. The aforementioned 18 genes also showed significant correlation with cells of the tumor immune microenvironment (TIME) such as NK, CD8+ T cells, and neutrophils, a possible route these genes may modulate survival. Previous work on hepatocellular carcinoma have demonstrated that the TIME has an impact on treatment efficacy. Thus, our findings warrant further experimental validation as it may suggest therapeutic approaches for ccRCC.