Integrative genome-wide expression profiling identifies three distinct molecular subgroups of renal cell carcinoma with different patient outcome

Abstract

BackgroundRenal cell carcinoma (RCC) is characterized by a number of diverse molecular aberrations that differ among individuals. Recent approaches to molecularly classify RCC were based on clinical, pathological as well as on single molecular parameters. As a consequence, gene expression patterns reflecting the sum of genetic aberrations in individual tumors may not have been recognized. In an attempt to uncover such molecular features in RCC, we used a novel, unbiased and integrative approach.MethodsWe integrated gene expression data from 97 primary RCC of different pathologic parameters, 15 RCC metastases as well as 34 cancer cell lines for two-way nonsupervised hierarchical clustering using gene groups suggested by the PANTHER Classification System. We depicted the genomic landscape of the resulted tumor groups by means of Single Nuclear Polymorphism (SNP) technology. Finally, the achieved results were immunohistochemically analyzed using a tissue microarray (TMA) composed of 254 RCC.ResultsWe found robust, genome wide expression signatures, which split RCC into three distinct molecular subgroups. These groups remained stable even if randomly selected gene sets were clustered. Notably, the pattern obtained from RCC cell lines was clearly distinguishable from that of primary tumors. SNP array analysis demonstrated differing frequencies of chromosomal copy number alterations among RCC subgroups. TMA analysis with group-specific markers showed a prognostic significance of the different groups.ConclusionWe propose the existence of characteristic and histologically independent genome-wide expression outputs in RCC with potential biological and clinical relevance.

pVHL/HIF-Regulated CD70 Expression Is Associated with Infiltration of CD27+ Lymphocytes and Increased Serum Levels of Soluble CD27 in Clear Cell Renal Cell Carcinoma

“…5A). CD27 and CD70 gene expression obtained from a recent DNA-microarray analysis (20) confirmed this finding (Fig. 5B).…”

“…Gene expression data of 116 RCCs and six normal kidneys were obtained from a recently published microarray study (20). Microarray data are available in Gene Expression Omnibus under GSE19949.…”

“…Gene expression analysis of 116 RCC tissues (20) revealed that CD70 was upregulated in primary and metastatic ccRCC (Fig. 1A).…”

miR-28-5p Promotes Chromosomal Instability in VHL-Associated Cancers by Inhibiting Mad2 Translation

“…S7A). Even more importantly, aneuploidy levels, expressed as the variance of chromosome copy numbers from SNP data (31), correlate linearly with miR-28-5p expression levels in ccRCC stratified by grade ( Fig. 7D and Supplementary Fig.…”

Microarrays and Renal Cell Cancer Biomarkers

“…An example showing hierarchical clustering of genes in ccRCC and pRCC (Beleut et al 2012) is shown in Fig. 4.…”