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- Brannon, A Rose, et al.
(författare)
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Molecular Stratification of Clear Cell Renal Cell Carcinoma by Consensus Clustering Reveals Distinct Subtypes and Survival Patterns.
- 2010
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Ingår i: Genes & cancer. - : Sage. - 1947-6027 .- 1947-6019. ; 1:2, s. 152-163
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Tidskriftsartikel (refereegranskat)abstract
- Clear cell renal cell carcinoma (ccRCC) is the predominant RCC subtype, but even within this classification, the natural history is heterogeneous and difficult to predict. A sophisticated understanding of the molecular features most discriminatory for the underlying tumor heterogeneity should be predicated on identifiable and biologically meaningful patterns of gene expression. Gene expression microarray data were analyzed using software that implements iterative unsupervised consensus clustering algorithms to identify the optimal molecular subclasses, without clinical or other classifying information. ConsensusCluster analysis identified two distinct subtypes of ccRCC within the training set, designated clear cell type A (ccA) and B (ccB). Based on the core tumors, or most well-defined arrays, in each subtype, logical analysis of data (LAD) defined a small, highly predictive gene set that could then be used to classify additional tumors individually. The subclasses were corroborated in a validation data set of 177 tumors and analyzed for clinical outcome. Based on individual tumor assignment, tumors designated ccA have markedly improved disease-specific survival compared to ccB (median survival of 8.6 vs 2.0 years, P = 0.002). Analyzed by both univariate and multivariate analysis, the classification schema was independently associated with survival. Using patterns of gene expression based on a defined gene set, ccRCC was classified into two robust subclasses based on inherent molecular features that ultimately correspond to marked differences in clinical outcome. This classification schema thus provides a molecular stratification applicable to individual tumors that has implications to influence treatment decisions, define biological mechanisms involved in ccRCC tumor progression, and direct future drug discovery.
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| 2. |
- Jamshidi, Neema, et al.
(författare)
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The Radiogenomic Risk Score : construction of a Prognostic Quantitative, Noninvasive Image-based Molecular Assay for Renal Cell Carcinoma
- 2015
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 0033-8419 .- 1527-1315. ; 277:1, s. 114-123
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image.Materials and Methods: In this institutional review board approved study, gene expression profile data and contrast material–enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression–based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis.Results: Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57,P < .001, classification accuracy 70.1%, P < .001) and predicted disease-specific survival (log rank P < .001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P < .001, classification accuracy 68.6%, P < .001) and disease-specific survival (log-rank P < .001) and that it was independent of stage, grade, and performance status (multivariate Cox model P < .05, log-rank P < .001).Conclusion: A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible.
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| 3. |
- Williams, Ariel A, et al.
(författare)
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CD9 and vimentin distinguish clear cell from chormophobe renal cell carcinoma.
- 2009
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Ingår i: BMC Clinical Pathology. - : Springer Science and Business Media LLC. - 1472-6890. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clear cell renal cell carcinoma (ccRCC) and chromophobe renal cell carcinoma(chRCC) can usually be distinguished by histologic characteristics. Occasionally, diagnosis proveschallenging and diagnostic difficulty will likely increase as needle biopsies of renal lesions becomemore common.Methods: To identify markers that aid in differentiating ccRCC from chRCC, we used geneexpression profiles to identify candidate markers that correlate with histology. 39 antisera andantibodies, including 35 for transcripts identified from gene expression profiling, were evaluated.Promising markers were tested on a tissue microarray (TMA) containing 428 renal neoplasms.Strength of staining of each core on the TMA was formally scored and the distribution of stainingacross different types of renal neoplasms was analyzed.Results: Based on results from initial immunohistochemical staining of multitissue titer arrays, 23of the antisera and antibodies were selected for staining of the TMA. For 7 of these markers,strength of staining of each core on the TMA was formally scored. Vimentin (positive in ccRCC)and CD9 (positive in chRCC) best distinguished ccRCC from chRCC. The combination of vimentinnegativity and CD9 positivity was found to distinguish chRCC from ccRCC with a sensitivity of100.0% and a specificity of 95.2%.Conclusion: Based on gene expression analysis, we identify CD9 and vimentin as candidatemarkers for distinguishing between ccRCC and chRCC. In difficult cases and particularly when theamount of diagnostic tissue is limited, vimentin and CD9 staining could serve as a useful adjunct inthe differential diagnosis of ccRCC and chRCC.
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| 4. |
- Zhao, Hongjuan, et al.
(författare)
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Alteration of gene expression signatures of cortical differentiation and wound response in lethal clear cell renal cell carcinomas.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:6, s. e6039-
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Tidskriftsartikel (refereegranskat)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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