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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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Weighted scaling expression of CSR genes distinguished ccRCC patients with better survival vs. poor survival.(A) Heat map of CSR gene expression in 177 ccRCC patients. CSR genes were separated into up- and down-sublists based on their response to serum. ccRCC samples were sorted by the sum of CSR gene expression ratios in each tumor calculated while taking into account their direction of changes in response to serum. (B) Kaplan-Meier estimates of disease-specific survival of two groups of ccRCC patients defined using the median of the weighted scaling expression of CSR genes as a cutoff.
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pone-0006039-g004: Weighted scaling expression of CSR genes distinguished ccRCC patients with better survival vs. poor survival.(A) Heat map of CSR gene expression in 177 ccRCC patients. CSR genes were separated into up- and down-sublists based on their response to serum. ccRCC samples were sorted by the sum of CSR gene expression ratios in each tumor calculated while taking into account their direction of changes in response to serum. (B) Kaplan-Meier estimates of disease-specific survival of two groups of ccRCC patients defined using the median of the weighted scaling expression of CSR genes as a cutoff.

Mentions: We further examined the predictive power of CSR genes using an alternative weighted scaling method. Specifically, a CSR index score was calculated for each sample by summing up the expression ratios taking into account the direction of regulation of each gene by serum treatment (see Methods). We sorted the tumors by their CSR index score and grouped the genes by their direction of change in response to serum treatment (Figure 4A). Tumors with high CSR scores were those that displayed gene expression similar to wound healing (i.e. high expression of genes upregulated by serum stimulation and low expression of genes downregulated by serum stimulation). We separated the 177 tumors into two groups using the median CSR index score as the cutoff. Kaplan-Meier analysis using this grouping criterion showed tumors with high CSR scores had significant lower cancer-specific survival than those with low CSR scores (pā€Š=ā€Š0.0007) (Figure 4B). These results confirmed that activation of the wound-healing gene expression signature is associated with poor survival in ccRCC patients.


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

Zhao H - PLoS ONE (2009)

Weighted scaling expression of CSR genes distinguished ccRCC patients with better survival vs. poor survival.(A) Heat map of CSR gene expression in 177 ccRCC patients. CSR genes were separated into up- and down-sublists based on their response to serum. ccRCC samples were sorted by the sum of CSR gene expression ratios in each tumor calculated while taking into account their direction of changes in response to serum. (B) Kaplan-Meier estimates of disease-specific survival of two groups of ccRCC patients defined using the median of the weighted scaling expression of CSR genes as a cutoff.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2698218&req=5

pone-0006039-g004: Weighted scaling expression of CSR genes distinguished ccRCC patients with better survival vs. poor survival.(A) Heat map of CSR gene expression in 177 ccRCC patients. CSR genes were separated into up- and down-sublists based on their response to serum. ccRCC samples were sorted by the sum of CSR gene expression ratios in each tumor calculated while taking into account their direction of changes in response to serum. (B) Kaplan-Meier estimates of disease-specific survival of two groups of ccRCC patients defined using the median of the weighted scaling expression of CSR genes as a cutoff.
Mentions: We further examined the predictive power of CSR genes using an alternative weighted scaling method. Specifically, a CSR index score was calculated for each sample by summing up the expression ratios taking into account the direction of regulation of each gene by serum treatment (see Methods). We sorted the tumors by their CSR index score and grouped the genes by their direction of change in response to serum treatment (Figure 4A). Tumors with high CSR scores were those that displayed gene expression similar to wound healing (i.e. high expression of genes upregulated by serum stimulation and low expression of genes downregulated by serum stimulation). We separated the 177 tumors into two groups using the median CSR index score as the cutoff. Kaplan-Meier analysis using this grouping criterion showed tumors with high CSR scores had significant lower cancer-specific survival than those with low CSR scores (pā€Š=ā€Š0.0007) (Figure 4B). These results confirmed that activation of the wound-healing gene expression signature is associated with poor survival in ccRCC patients.

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