Abstract
The heterogeneity of renal cell carcinoma (RCC) subtypes reflects the cell type of origin in the nephron, with consequences for therapy and prognosis. The transcriptional cues that determine segment-specific gene expression patterns are poorly understood. We recently showed that hypertonicity in the renal medulla regulates nephron-specific gene expression. Here, we analyzed a set of 223 genes, which were identified in the present study by RNA-Seq to be differentially expressed by hypertonicity, for the prediction of cancer-specific survival (CSS). Cluster analyses of these genes showed discrimination between tumor and non-tumor samples of clear cell RCC (ccRCC). Refinement of this gene signature to a four-gene score (OSM score) through statistical analyses enabled prediction of CSS in ccRCC patients of The Cancer Genome Atlas (TCGA) (n = 436) in univariate (HR = 4.1; 95% CI: 2.78−6.07; p = 4.39 × 10−13), and multivariate analyses including primary tumor (T); regional lymph node (N); distant metastasis (M); grading (G)(p = 2.3 × 10−5). The OSM score could be validated in an independent ccRCC study (n = 52) in univariate (HR = 1.29; 95% CI = 1.05–1.59; p = 0.011) and multivariate analyses (p = 0.016). Cell culture experiments using RCC cell lines demonstrated that the expression of the tumor suppressor ELF5 could be restored by hypertonicity. The innovation of our novel gene signature is that these genes are physiologically regulated only by hypertonicity, thereby providing the possibility to be targeted for therapy.
Highlights
The kidney’s anatomy and histology consists of different renal cell types located at defined parts of the kidneys, reflected in the complexity of renal function
Both studies used data based on nephron-specific gene expression patterns and were able either to improve the prediction of patient outcome or identify gene expression networks defining the origin of renal cell carcinoma (RCC)
In contrast to our initial study, where we used microarrays, here we performed RNA-Seq using primary cultured inner medullary collecting duct (IMCD) cells cultivated at 300 or 900 mosmol/kg to identify differentially expressed transcripts affected by hypertonicity
Summary
The kidney’s anatomy and histology consists of different renal cell types located at defined parts of the kidneys, reflected in the complexity of renal function This is reflected by the heterogeneity of renal cell carcinoma (RCC) subtypes [1]. The authors were able to identify gene expression programs that were specific for a distinct nephron segment and were present in the corresponding RCC subtypes Both studies used data based on nephron-specific gene expression patterns and were able either to improve the prediction of patient outcome or identify gene expression networks defining the origin of RCC. We analyzed if the hypertonicity-affected genes were differentially expressed in ccRCC tumor samples and normal tissue, and if these genes were associated with the clinical outcome of the patients
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