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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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Expression of normal cortex genes predicts survival in ccRCC.(A) Supervised hierarchical clustering analysis of the expression patterns of 67 cortex genes represented by 87 transcripts in 177 ccRCCs. Each row represents a single gene, and each column a patient sample. The degree of color saturation corresponds to the ratio of gene expression in each sample compared to the mean expression across all samples. The distributions of the scaled gene expression scores 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 cortex gene expression. (C) Kaplan-Meier estimates of overall survival of two main groups of ccRCC patients defined in (A) based on the cortex gene expression.
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pone-0006039-g001: Expression of normal cortex genes predicts survival in ccRCC.(A) Supervised hierarchical clustering analysis of the expression patterns of 67 cortex genes represented by 87 transcripts in 177 ccRCCs. Each row represents a single gene, and each column a patient sample. The degree of color saturation corresponds to the ratio of gene expression in each sample compared to the mean expression across all samples. The distributions of the scaled gene expression scores 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 cortex gene expression. (C) Kaplan-Meier estimates of overall survival of two main groups of ccRCC patients defined in (A) based on the cortex gene expression.

Mentions: Although the SPC gene set was highly prognostic, analysis of the known functions of each of the 259 genes in this set did not reveal common pathways or biological themes that could provide insights into the biology of lethal ccRCC [6]. To gain insights, we compared the SPC gene set to another gene expression data set identified by profiling different anatomical segments of the normal kidney including the glomeruli, cortex, medulla, papillary tips, and pelvis. The expression patterns of these genes represent the transcriptional programs intrinsic to each of these kidney segments in their normal, fully differentiated state. The cortex signature consists of 190 named unique genes represented by 260 clones, out of which 25 named genes were found in SPC gene list (Figure 1A). This overlap (or enrichment) was statistically significant by permutation test (p<10−4 by 1,000,000 permutations). Specifically, the number of genes that overlap between the cortex and SPC genes was significantly greater than that of random gene sets of the same sizes (190 as cortex genes and 259 as SPC genes) drawn independently from the total gene pool from which the cortex and SPC genes were identified. Ten out of 132 transcripts highly expressed in the glomerulus were found in the SPC gene list, representing a significant overlap between the two gene lists although to a lesser degree than the cortex genes (p = 0.005 by 1,000,000 permutations). The glomeruli are located exclusively in the normal renal cortex and genes expressed in isolated glomeruli reflect additional expression features of differentiated normal renal cortex. No significant overlap was found between SPC gene set and gene lists from other anatomic segments of the kidney. Specifically, 2 of 425 transcripts highly expressed in the renal pelvis were found in SPC gene list and none of the transcripts highly expressed in the medulla or papillary tips were found in the SPC gene list. All individual gene lists and overlapping genes are provided in Supplemental file S1.


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

Zhao H - PLoS ONE (2009)

Expression of normal cortex genes predicts survival in ccRCC.(A) Supervised hierarchical clustering analysis of the expression patterns of 67 cortex genes represented by 87 transcripts in 177 ccRCCs. Each row represents a single gene, and each column a patient sample. The degree of color saturation corresponds to the ratio of gene expression in each sample compared to the mean expression across all samples. The distributions of the scaled gene expression scores 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 cortex gene expression. (C) Kaplan-Meier estimates of overall survival of two main groups of ccRCC patients defined in (A) based on the cortex gene expression.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2698218&req=5

pone-0006039-g001: Expression of normal cortex genes predicts survival in ccRCC.(A) Supervised hierarchical clustering analysis of the expression patterns of 67 cortex genes represented by 87 transcripts in 177 ccRCCs. Each row represents a single gene, and each column a patient sample. The degree of color saturation corresponds to the ratio of gene expression in each sample compared to the mean expression across all samples. The distributions of the scaled gene expression scores 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 cortex gene expression. (C) Kaplan-Meier estimates of overall survival of two main groups of ccRCC patients defined in (A) based on the cortex gene expression.
Mentions: Although the SPC gene set was highly prognostic, analysis of the known functions of each of the 259 genes in this set did not reveal common pathways or biological themes that could provide insights into the biology of lethal ccRCC [6]. To gain insights, we compared the SPC gene set to another gene expression data set identified by profiling different anatomical segments of the normal kidney including the glomeruli, cortex, medulla, papillary tips, and pelvis. The expression patterns of these genes represent the transcriptional programs intrinsic to each of these kidney segments in their normal, fully differentiated state. The cortex signature consists of 190 named unique genes represented by 260 clones, out of which 25 named genes were found in SPC gene list (Figure 1A). This overlap (or enrichment) was statistically significant by permutation test (p<10−4 by 1,000,000 permutations). Specifically, the number of genes that overlap between the cortex and SPC genes was significantly greater than that of random gene sets of the same sizes (190 as cortex genes and 259 as SPC genes) drawn independently from the total gene pool from which the cortex and SPC genes were identified. Ten out of 132 transcripts highly expressed in the glomerulus were found in the SPC gene list, representing a significant overlap between the two gene lists although to a lesser degree than the cortex genes (p = 0.005 by 1,000,000 permutations). The glomeruli are located exclusively in the normal renal cortex and genes expressed in isolated glomeruli reflect additional expression features of differentiated normal renal cortex. No significant overlap was found between SPC gene set and gene lists from other anatomic segments of the kidney. Specifically, 2 of 425 transcripts highly expressed in the renal pelvis were found in SPC gene list and none of the transcripts highly expressed in the medulla or papillary tips were found in the SPC gene list. All individual gene lists and overlapping genes are provided in Supplemental file S1.

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