The Epithelial‐Mesenchymal Transition and Survival in Chromophobe Renal Cell Carcinoma

Abstract

Introduction and ObjectiveAdvances in our understanding of the epithelial‐mesenchymal transition (EMT), how cells change polarity and surface‐expressed proteins in acquiring a more malignant state, has aided scientists in understanding cancer progression. Using in silico tools, this study examines how EMT‐related gene expression levels are associated with survival outcomes in the rare chromophobe renal cell carcinoma (ChRCC).MethodsUsing dbEMT, a curated database examining EMT literature, 1184 genes were selected as “EMT‐related” for further analysis. Kaplain‐Meier Survival plots were generated based on TCGA data on all recorded ChRCC patients for each gene (n=32 in “high” and “low” groups each based on a median cut‐off), with the step‐up Bonferroni method for multiple hypothesis testing correction being used (significance being established at p<0.004). Genes identified to be statistically significant in terms of survival outcome were selected for enrichment analysis through Cytospace to examine which biological pathways might predict survival outcome. Network analysis based on physical and predicted interactions using GeneMANIA and R was done to generate a list of non‐EMT related genes which might act with those statistically significant EMT‐related genes to affect survival, with cut‐off for for significance of both network and enrichment analysis being p<0.01. DisGeNET was used to observe if the gene expression profile of ChRCC resembled any other kind of cancer.ResultsFrom the original 1184 genes, 13 showed significant change following multiple hypothesis testing correction (p<0.0038), with all showing an increased expression relating to worse outcomes. Nine distinct processes, ranging from histone modification to SMAD2/3 nuclear pathways among others, were significantly overrepresented (p<0.01) in those 13 genes. The significant EMT‐related gene signature in ChRCC mimicked the profile of mantle cell lymphoma and urothelial carcinoma. Network analysis highlighted more than 20 additional genes which EMT‐related genes could interact with to affect survival.ConclusionsThis study showcases a small subset of EMT‐related genes significantly overexpressed in ChRCC cases with worse prognosis. Analysis highlighted pathway dysfunction regarding microtubule cytoskeletal organization and histone modification (among others) as a possible cause of increased mortality in cases of chromophobe renal cell carcinoma. Such a preliminary in silico analysis would allow for strategically targeted wet‐lab studies.