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Alteration of gene expression signatures of cortical differentiation and wound response in lethal clear cell renal cell carcinomas.

Zhao H - PLoS ONE (2009)

Bottom Line: Tumors whose gene expression profiles most resembled the normal renal cortex or glomerulus showed better survival than those that did not, and those with expression features more similar to CSR showed poorer survival.While the cortex, glomerulus, and CSR signatures predicted survival independent of traditional clinical parameters, they were not independent of the SPC gene list.Our findings suggest that critical biological features of lethal ccRCC include loss of normal cortical differentiation and activation of programs associated with wound healing.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Stanford University, Stanford, CA, USA.

ABSTRACT
Clear cell renal cell carcinoma (ccRCC) is the most common malignancy of the adult kidney and displays heterogeneity in clinical outcomes. Through comprehensive gene expression profiling, we have identified previously a set of transcripts that predict survival following nephrectomy independent of tumor stage, grade, and performance status. These transcripts, designated as the SPC (supervised principal components) gene set, show no apparent biological or genetic features that provide insight into renal carcinogenesis or tumor progression. We explored the relationship of this gene list to a set of genes expressed in different anatomical segments of the normal kidney including the cortex (cortex gene set) and the glomerulus (glomerulus gene set), and a gene set expressed after serum stimulation of quiescent fibroblasts (the core serum response or CSR gene set). Interestingly, the normal cortex, glomerulus (part of the normal renal cortex), and CSR gene sets captured more than 1/5 of the genes in the highly prognostic SPC gene set. Based on gene expression patterns alone, the SPC gene set could be used to sort samples from normal adult kidneys by the anatomical regions from which they were dissected. Tumors whose gene expression profiles most resembled the normal renal cortex or glomerulus showed better survival than those that did not, and those with expression features more similar to CSR showed poorer survival. While the cortex, glomerulus, and CSR signatures predicted survival independent of traditional clinical parameters, they were not independent of the SPC gene list. Our findings suggest that critical biological features of lethal ccRCC include loss of normal cortical differentiation and activation of programs associated with wound healing.

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Hierarchical clustering based on core serum response (CSR) gene expression predicts survival in ccRCC.(A) Supervised hierarchical clustering analysis of the expression patterns of 353 CSR genes represented by 420 transcripts in 177 ccRCCs. The distributions of the scaled gene expression scores for the up- and down-sublists were shown below the heat map. (B) Kaplan-Meier estimates of disease-specific survival of two main groups of ccRCC patients defined in (A) based on the CSR gene expression. (C) Kaplan-Meier estimates of overall survival of two main groups of ccRCC patients defined in (A) based on the CSR gene expression.
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pone-0006039-g003: Hierarchical clustering based on core serum response (CSR) gene expression predicts survival in ccRCC.(A) Supervised hierarchical clustering analysis of the expression patterns of 353 CSR genes represented by 420 transcripts in 177 ccRCCs. The distributions of the scaled gene expression scores for the up- and down-sublists were shown below the heat map. (B) Kaplan-Meier estimates of disease-specific survival of two main groups of ccRCC patients defined in (A) based on the CSR gene expression. (C) Kaplan-Meier estimates of overall survival of two main groups of ccRCC patients defined in (A) based on the CSR gene expression.

Mentions: The transcriptional signature of the response of fibroblasts to serum has been shown to be a powerful predictor of the clinical course in several common carcinomas [9], [11]. The enrichment of CSR genes in SPC gene set suggests that CSR signature may predict survival in ccRCC and might reflect biological features captured in the SPC gene list. Out of the 400 unique genes in the core serum response signature, 353 represented by 420 transcripts were well measured and highly variable in the ccRCC data set (for a complete list of genes and expression level, see Supplemental file S4). Out of the 420 transcripts, 207 were downregulated (down-sublist) by serum treatment and 213 were upregulated (up-sublist). When average linkage hierarchical clustering analysis of the 177 patient samples was performed using this 353 genes, tumors were partitioned into two main groups (Figure 3A and Supplemental Figure S1). We calculated the sum of the expression ratios for the up- and down-sublist for each tumor, and the distributions of the sum for cluster 1 and cluster 2 were shown in Figure 3A. The majority of cluster 2 tumors showed high expression of the up-sublist and low expression of the down-sublist, suggesting an activation of serum response program. In addition, more cluster 1 tumors than cluster 2 tumors showed low expression of the up-sublist and high expression of the down-sublist, indicating an inversed expression of serum response program. Finally, in the cluster 1 tumors there was a small subset of tumors in which the up-sublist and many of the down-sublist of genes were expressed at a higher level, suggesting that the up- and down-sublists were not coordinately regulated in these tumors. Kaplan-Meier analysis showed that cluster 1 had higher cancer-specific (Figure 3B, p = 0.001, log-rank test) and overall survival (Figure 3C, p = 0.02, log-rank test) compared to cluster 2. The median overall survival for cluster 1 was 38 months and for cluster 2 was 25.5 months. The median disease specific survival for cluster 1 was 38 months and for cluster 2 was 27 months. These results suggest that activation of the CSR gene expression program predicts ccRCC survival.


Alteration of gene expression signatures of cortical differentiation and wound response in lethal clear cell renal cell carcinomas.

Zhao H - PLoS ONE (2009)

Hierarchical clustering based on core serum response (CSR) gene expression predicts survival in ccRCC.(A) Supervised hierarchical clustering analysis of the expression patterns of 353 CSR genes represented by 420 transcripts in 177 ccRCCs. The distributions of the scaled gene expression scores for the up- and down-sublists were shown below the heat map. (B) Kaplan-Meier estimates of disease-specific survival of two main groups of ccRCC patients defined in (A) based on the CSR gene expression. (C) Kaplan-Meier estimates of overall survival of two main groups of ccRCC patients defined in (A) based on the CSR gene expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2698218&req=5

pone-0006039-g003: Hierarchical clustering based on core serum response (CSR) gene expression predicts survival in ccRCC.(A) Supervised hierarchical clustering analysis of the expression patterns of 353 CSR genes represented by 420 transcripts in 177 ccRCCs. The distributions of the scaled gene expression scores for the up- and down-sublists were shown below the heat map. (B) Kaplan-Meier estimates of disease-specific survival of two main groups of ccRCC patients defined in (A) based on the CSR gene expression. (C) Kaplan-Meier estimates of overall survival of two main groups of ccRCC patients defined in (A) based on the CSR gene expression.
Mentions: The transcriptional signature of the response of fibroblasts to serum has been shown to be a powerful predictor of the clinical course in several common carcinomas [9], [11]. The enrichment of CSR genes in SPC gene set suggests that CSR signature may predict survival in ccRCC and might reflect biological features captured in the SPC gene list. Out of the 400 unique genes in the core serum response signature, 353 represented by 420 transcripts were well measured and highly variable in the ccRCC data set (for a complete list of genes and expression level, see Supplemental file S4). Out of the 420 transcripts, 207 were downregulated (down-sublist) by serum treatment and 213 were upregulated (up-sublist). When average linkage hierarchical clustering analysis of the 177 patient samples was performed using this 353 genes, tumors were partitioned into two main groups (Figure 3A and Supplemental Figure S1). We calculated the sum of the expression ratios for the up- and down-sublist for each tumor, and the distributions of the sum for cluster 1 and cluster 2 were shown in Figure 3A. The majority of cluster 2 tumors showed high expression of the up-sublist and low expression of the down-sublist, suggesting an activation of serum response program. In addition, more cluster 1 tumors than cluster 2 tumors showed low expression of the up-sublist and high expression of the down-sublist, indicating an inversed expression of serum response program. Finally, in the cluster 1 tumors there was a small subset of tumors in which the up-sublist and many of the down-sublist of genes were expressed at a higher level, suggesting that the up- and down-sublists were not coordinately regulated in these tumors. Kaplan-Meier analysis showed that cluster 1 had higher cancer-specific (Figure 3B, p = 0.001, log-rank test) and overall survival (Figure 3C, p = 0.02, log-rank test) compared to cluster 2. The median overall survival for cluster 1 was 38 months and for cluster 2 was 25.5 months. The median disease specific survival for cluster 1 was 38 months and for cluster 2 was 27 months. These results suggest that activation of the CSR gene expression program predicts ccRCC survival.

Bottom Line: Tumors whose gene expression profiles most resembled the normal renal cortex or glomerulus showed better survival than those that did not, and those with expression features more similar to CSR showed poorer survival.While the cortex, glomerulus, and CSR signatures predicted survival independent of traditional clinical parameters, they were not independent of the SPC gene list.Our findings suggest that critical biological features of lethal ccRCC include loss of normal cortical differentiation and activation of programs associated with wound healing.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Stanford University, Stanford, CA, USA.

ABSTRACT
Clear cell renal cell carcinoma (ccRCC) is the most common malignancy of the adult kidney and displays heterogeneity in clinical outcomes. Through comprehensive gene expression profiling, we have identified previously a set of transcripts that predict survival following nephrectomy independent of tumor stage, grade, and performance status. These transcripts, designated as the SPC (supervised principal components) gene set, show no apparent biological or genetic features that provide insight into renal carcinogenesis or tumor progression. We explored the relationship of this gene list to a set of genes expressed in different anatomical segments of the normal kidney including the cortex (cortex gene set) and the glomerulus (glomerulus gene set), and a gene set expressed after serum stimulation of quiescent fibroblasts (the core serum response or CSR gene set). Interestingly, the normal cortex, glomerulus (part of the normal renal cortex), and CSR gene sets captured more than 1/5 of the genes in the highly prognostic SPC gene set. Based on gene expression patterns alone, the SPC gene set could be used to sort samples from normal adult kidneys by the anatomical regions from which they were dissected. Tumors whose gene expression profiles most resembled the normal renal cortex or glomerulus showed better survival than those that did not, and those with expression features more similar to CSR showed poorer survival. While the cortex, glomerulus, and CSR signatures predicted survival independent of traditional clinical parameters, they were not independent of the SPC gene list. Our findings suggest that critical biological features of lethal ccRCC include loss of normal cortical differentiation and activation of programs associated with wound healing.

Show MeSH
Related in: MedlinePlus