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Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness.

ABSTRACT: BACKGROUND:Intratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored. OBJECTIVE:To evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors. DESIGN, SETTING, AND PARTICIPANTS:We identified 111 patients who had tissue available from their primary tumor and at least one metastasis. ClearCode34 genes were analyzed for all tumors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Primary and metastatic tumors were classified as clear cell type A (ccA) or B (ccB) subtypes. Logistic and Cox regression were used to evaluate associations with pathologic features and survival. RESULTS AND LIMITATIONS:Intratumor heterogeneity of ccA/ccB subtypes was observed in 22% (95% confidence interval [CI] 3-60%) of metastatic tumors. Subtype differed across longitudinal metastatic tumors from the same patient in 23% (95% CI 10-42%) of patients and across patient-matched primary and metastatic tumors in 43% (95% CI 32-55%) of patients. Association of subtype with survival was validated in primary ccRCC tumors. The ccA/ccB subtype in metastatic tumors was significantly associated with metastatic tumor location, metastatic tumor grade, and presence of tumor necrosis. A limitation of this study is that we only analyzed patients who had both a nephrectomy and metastasectomy. CONCLUSIONS:Approximately one quarter of metastatic tumors displayed intratumor heterogeneity; a similar rate of heterogeneity was observed across longitudinal metastatic tumors. Thus, for biomarker studies it is likely adequate to analyze a single sample per metastatic tumor provided that pathologic review is incorporated into the study design. Subtypes across patient-matched primary and metastatic tumors differed 43% of the time, suggesting that the primary tumor is not a good surrogate for the metastatic tumor. PATIENT SUMMARY:Primary and secondary/metastatic cancers of the kidney differed in nearly one half of ccRCC patients. The pattern of this relationship may affect tumor growth and the most suitable treatment.

SUBMITTER: Serie DJ

PROVIDER: S-EPMC5401797 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness.

Serie Daniel J DJ Joseph Richard W RW Cheville John C JC Ho Thai H TH Parasramka Mansi M Hilton Tracy T Thompson R Houston RH Leibovich Bradley C BC Parker Alexander S AS Eckel-Passow Jeanette E JE

European urology 20161126 6

<h4>Background</h4>Intratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored.<h4>Objective</h4>To evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors.<h4>Design, setting, and participants</h4>We identified 111 patients who had tissue available from their primary tumor and at least one metastasis. ClearCode34 genes were analyzed for ...[more]

PMID: 27899233

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Project description:Renal cell carcinoma (RCC) is one of the leading causes of cancer-related death worldwide. Tumour metastasis and heterogeneity lead to poor survival outcomes and drug resistance in patients with metastatic RCC (mRCC). In this study, we aimed to assess intratumoural heterogeneity (ITH) in mRCC cells by performing a combined analysis of bulk data and single-cell RNA-sequencing data, and develop novel biomarkers for prognosis prediction on the basis of the potential molecular mechanisms underlying tumorigenesis. Eligible single-cell cohorts related to mRCC were acquired using the Gene Expression Omnibus (GEO) dataset to identify potential mRCC subpopulations. We then performed gene set variation analysis to understand the differential function in primary RCC and mRCC samples. Subsequently, we applied weighted correlation network analysis to identify coexpressing gene modules that were related to the external trait of metastasis. Protein-protein interactions were used to screen hub subpopulation-difference (sub-dif) markers (ACTG1, IL6, CASP3, ACTB and RAP1B) that might be involved in the regulation of RCC metastasis and progression. Cox regression analysis revealed that ACTG1 was a protective factor (HR < 1), whereas the other four genes (IL6, CASP3, ACTB and RAP1B) were risk factors (HR > 1). Kaplan-Meier survival analysis suggested the potential prognostic value of these sub-dif markers. The expression of sub-dif markers in mRCC was further evaluated in clinical samples by immunohistochemistry (IHC). Additionally, the genetic features of sub-dif marker expression patterns, such as genetic variation profiles, correlations with tumour-infiltrating lymphocytes (TILs), and targeted signalling pathway activities, were assessed in bulk RNA-seq datasets. In conclusion, we established novel subpopulation markers as key prognostic factors affecting EMT-related signalling pathway activation in mRCC, which could facilitate the implementation of a treatment for mRCC patients.

Dataset Information

Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness.

Publications

Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness.

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