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Characterizing the molecular heterogeneity of clear cell renal cell carcinoma subgroups classified by miRNA expression profile.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is a heterogeneous disease that is associated with poor prognosis. Recent works have revealed the significant roles of miRNA in ccRCC initiation and progression. Comprehensive characterization of ccRCC based on the prognostic miRNAs would contribute to clinicians' early detection and targeted treatment. Here, we performed unsupervised clustering using TCGA-retrieved prognostic miRNAs expression profiles. Two ccRCC subtypes were identified after assessing principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), and consensus heatmaps. We found that the two subtypes are associated with distinct clinical features, overall survivals, and molecular characteristics. C1 cluster enriched patients in relatively early stage and have better prognosis while patients in C2 cluster have poor prognosis with relatively advanced state. Mechanistically, we found the differentially expressed genes (DEGs) between the indicated subgroups dominantly enriched in biological processes related to transmembrane transport activity. In addition, we also revealed a miRNA-centered DEGs regulatory network, which severed as essential regulators in both transmembrane transport activity control and ccRCC progression. Together, our work described the molecular heterogeneity among ccRCC cancers, provided potential targets served as effective biomarkers for ccRCC diagnosis and prognosis, and paved avenues to better understand miRNA-directed regulatory network in ccRCC progression.

SUBMITTER: Shen T

PROVIDER: S-EPMC9459094 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Characterizing the molecular heterogeneity of clear cell renal cell carcinoma subgroups classified by miRNA expression profile.

Shen Tao T Song Yingdong Y Wang Xiangting X Wang Haiyang H

Frontiers in molecular biosciences 20220826

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous disease that is associated with poor prognosis. Recent works have revealed the significant roles of miRNA in ccRCC initiation and progression. Comprehensive characterization of ccRCC based on the prognostic miRNAs would contribute to clinicians' early detection and targeted treatment. Here, we performed unsupervised clustering using TCGA-retrieved prognostic miRNAs expression profiles. Two ccRCC subtypes were identified after assessing p ...[more]

PMID: 36090028

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Project description:BackgroundRenal cell carcinoma (RCC) can exhibit a unique vascular tropism that enables tumor thrombus extension into the inferior vena cava (IVC). While most RCC subtypes that form tumor thrombi are of clear cell (cc) histology, non-clear cell (ncc) subtypes can also exhibit this unique growth pattern.ObjectiveTo characterize clinicopathologic differences and survival outcomes among patients with IVC tumor thrombus arising from ccRCC versus nccRCC.Design setting and participantsPatients diagnosed with IVC tumor thrombus secondary to RCC in our institutional experience from 2003 to 2021 were identified.Outcome measurements and statistical analysisClinicopathologic characteristics were compared by histology. Perioperative and oncologic outcomes including recurrence-free (RFS), overall (OS), and cancer-specific (CSS) survival were assessed using multivariable Cox regression analyses.Results and limitationsThe analyzed cohort included 103 patients (82 ccRCC and 21 nccRCC). There were no significant differences in baseline demographic parameters. Patients with nccRCC were more likely to have regional lymph node involvement (42.9% vs 20.7%, p = 0.037). No differences in perioperative outcomes, IVC resection, or IVC reconstruction were observed between groups. The median follow-up time was 30 mo. The median RFS was 30 (nccRCC) versus 53 (ccRCC) mo (p = 0.1). There was no significant difference in OS or CSS. This study was limited by its small sample size.ConclusionsPatients with IVC tumor thrombus arising from ccRCC and nccRCC exhibit similar perioperative and oncologic outcomes. While surgical appropriateness was not impacted by histologic subtype, multimodal strategies are needed to improve outcomes for patients with tumor thrombus.Patient summaryRenal cell carcinoma (RCC) can uniquely invade vasculature and form a tumor thrombus. This study examined the difference in outcomes of patients with tumor thrombus based on RCC subtype (clear cell vs non-clear cell). We found that patients exhibited similar surgical and survival outcomes regardless of RCC type.

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.

Project description:BackgroundIntratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored.ObjectiveTo evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors.Design, setting, and participantsWe 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 analysisPrimary 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 limitationsIntratumor 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.ConclusionsApproximately 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 summaryPrimary 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.

Dataset Information

Characterizing the molecular heterogeneity of clear cell renal cell carcinoma subgroups classified by miRNA expression profile.

Publications

Characterizing the molecular heterogeneity of clear cell renal cell carcinoma subgroups classified by miRNA expression profile.

Similar Datasets

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