Profiling micro<scp>RNA</scp> from nephrectomy and biopsy specimens: predictors of progression and survival in clear cell renal cell carcinoma

Kowalik, Casey G.; Palmer, Drew; Sullivan, Travis; Teebagy, Patrick; Dugan, John M.; Libertino, John A.; Burks, Eric; Canes, David; Rieger-Christ, Kimberly

doi:10.1111/bju.13886

Cited by 29 publications

(12 citation statements)

References 31 publications

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“…Over the last decade, the frequency of incidentally detected RCC has significantly increased, mostly due to the widespread use of imaging techniques. CcRCC, the most prevalent RCC, carries worse prognosis than other common RCC subtypes, as approximately 20-40% of cases develop distant metastases [7], which are the main cause of RCC-related mortality, the highest among urologic cancers [26,27]. Thus, biomarkers capable of accurately identifying ccRCC cases prone to metastasize, mostly among early stage tumors at diagnosis, would be a major clinical breakthrough.…”

Section: Discussionmentioning

confidence: 99%

“…It comprises 70-75% of all RCC cases and is characterized by several distinct genetic and epigenetic alterations [6]. About 25% of ccRCC patients present distant metastases at time of diagnosis, and in 20-50%, metastatic disease develops few years after diagnosis and surgical treatment of the primary tumor [3,5,7,8]. Furthermore, ccRCC is extremely resistant to radiation and to conventional chemotherapy [3].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, metastatic dissemination is the most important prognostic factor in ccRCC [10], highlighting the importance of accurately identifying patients at high risk of disease progression. Moreover, the identification of molecular biomarkers that might indicate risk of disease progression (recurrence, metastization) at the time of diagnosis might improve clinical management [3,7] effectively contributing to implementation of Precision Medicine [10].…”

Section: Introductionmentioning

confidence: 99%

“…MiRs' deregulation has been shown to participate in tumorigenesis, affecting differentiation, invasion, migration and apoptosis [10,14] and has been implicated in urological tumors [15]. Several studies have associated microRNAs (miRs) deregulation with ccRCC clinicopathological features, suggesting a role in tumor initiation and progression [5,7,16,17]. MiR-30a-5p, an intergenic miR (chromosome 6, 71,403,551-71,403,621 [− strand]), was suggested to play a role in cellular differentiation and development [18], but its precise role remains largely unknown [19,20].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-30a-5pme: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples

Outeiro-Pinho

Barros‐Silva

Aznar

et al. 2020

J Exp Clin Cancer Res

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Background: The rising incidence of renal cell carcinomas (RCC) constitutes a significant challenge owing to risk of overtreatment. Because aberrant microRNA (miR) promoter methylation contributes to cancer development, we investigated whether altered miR-30a-5p expression associates with DNA promoter methylation and evaluated the usefulness as clear cell RCC (ccRCC) diagnostic and prognostic markers. Methods: Genome-wide methylome and RNA sequencing data from a set of ccRCC and normal tissue samples from The Cancer Genome Atlas (TCGA) database were integrated to identify candidate CpG loci involved in cancer onset. MiR-30a-5p expression and promoter methylation were quantitatively assessed by PCR in a tissue set (Cohort #1) and urine sets (Cohorts #2 and 3) from IPOPorto and Homburg University Hospital. Non-parametric tests were used for comparing continuous variables. MiR-30a-5p promoter methylation (miR-30a-5p me) performance as diagnostic (receiver operator characteristics [ROC]-validity estimates) and prognostic [metastasis-free (MFS) and disease-specific survival (DSS)] biomarker was further validated in urine samples from ccRCC patients by Kaplan Meier curves (with log rank) and both univariable and multivariable analysis. Results: Two significant hypermethylated CpG loci in TCGA ccRCC samples, correlating with miR-30a-5p transcriptional downregulation, were disclosed. MiR-30a-5p me in ccRCC tissues was confirmed in an independent patient's cohort of IPOPorto and associated with shorter time to relapse. In urine samples, miR-30a-5p me levels identified cancer both in testing and validation cohorts, with 83% sensitivity/53% specificity and 63% sensitivity/67% specificity, respectively. Moreover, higher miR-30a-5p me levels independently predicted metastatic dissemination and survival.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MicroRNA-30a-5pme: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples

Outeiro-Pinho

Barros‐Silva

Aznar

et al. 2020

J Exp Clin Cancer Res

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“…Heinzelmann et al identifizierten 14 miRNAs, die in metastasierten im Vergleich zu nicht metastasierten Primärtumoren differenziert exprimiert sind [25]. [28]. Diese 3 letztgenannten Studien untersuchten jedoch nicht den zusätzlichen Wert dieser Biomarker im Vergleich zu klinischen Parametern oder Scores und bleiben deshalb den Beweis der Überlegenheit der Biomarker schuldig.…”

Section: Subtypunclassified

Personalisierte Medizin bei Nierenzelltumoren

Junker

Zeuschner

2019

Aktuel Urol

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ZusammenfassungDie Entdeckung von immer kleineren Tumoren durch den umfassenden Einsatz von bildgebenden Verfahren, die Erweiterung der operativen Techniken und der systemischen Therapieoptionen fordern auch für Nierentumorpatienten eine Individualisierung der Therapie. Essenzielle Voraussetzung ist dabei die Kenntnis der Tumorbiologie, da sie eine differenzierte Diagnostik, individuelle Prognosebewertung und Therapiewahl, basierend auf Biomarkern, und die Entwicklung von neuen Therapiestrategien ermöglicht.Nierenzelltumore werden aktuell in 16 histologische Subtypen unterschieden, die durch spezifische genetische Veränderungen charakterisiert sind. Aufgrund ihrer unterschiedlichen Aggressivität ist die Kenntnis der Subtypen sowohl für die Therapieentscheidung als auch für die Nachsorge wichtig. Molekulare Marker können bei der Differenzialdiagnose eingesetzt werden. Molekulare Signaturen werden zukünftig aber auch wesentlich zur Prognosedifferenzierung innerhalb der Subtypen beitragen, wie für das klarzellige Nierenzellkarzinom bereits gezeigt wurde. Dies wird zur Entwicklung differenzierter Nachsorgeprotokolle und zu einer genaueren Selektion der Patienten für adjuvante Therapien führen. Für metastasierte Patienten stehen immer mehr medikamentöse Therapien zur Verfügung, die zielgerichtet in bestimmte zelluläre Signal- oder Kommunikationswege eingreifen. Auch wenn bisher noch keine validen prädiktiven Biomarker verfügbar sind, liegen vielversprechende Daten zu molekularen Signaturen in Korrelation mit dem Ansprechen auf Tyrosinkinaseinhibitoren oder Checkpointinhibitoren vor, die in Zukunft wesentlich besser als die klinischen Scores eine individuelle Therapiewahl ermöglichen werden.Zur Überführung der vielversprechenden Biomarker in die klinische Praxis sind nun prospektive multizentrische Studien erforderlich. Die Berücksichtigung von bereits vorhandenen Erkenntnissen aus der Tumorbiologie der verschiedenen NZK-Entitäten sowohl bez. der veränderten Signalwege in den Tumorzellen selbst als auch der Rolle des Mikromilieus einschließlich der Immunzellen ist eine essenzielle Voraussetzung für eine weitere Verbesserung von Diagnostik und Therapie.

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An in vitro approach to understand contribution of kidney cells to human urinary extracellular vesicles

Barreiro

Lay

Leparc

et al. 2023

J of Extracellular Vesicle

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Extracellular vesicles (EV) are membranous particles secreted by all cells and found in body fluids. Established EV contents include a variety of RNA species, proteins, lipids and metabolites that are considered to reflect the physiological status of their parental cells. However, to date, little is known about cell‐type enriched EV cargo in complex EV mixtures, especially in urine. To test whether EV secretion from distinct human kidney cells in culture differ and can recapitulate findings in normal urine, we comprehensively analysed EV components, (particularly miRNAs, long RNAs and protein) from conditionally immortalised human kidney cell lines (podocyte, glomerular endothelial, mesangial and proximal tubular cells) and compared to EV secreted in human urine. EV from cell culture media derived from immortalised kidney cells were isolated by hydrostatic filtration dialysis (HFD) and characterised by electron microscopy (EM), nanoparticle tracking analysis (NTA) and Western blotting (WB). RNA was isolated from EV and subjected to miRNA and RNA sequencing and proteins were profiled by tandem mass tag proteomics. Representative sets of EV miRNAs, RNAs and proteins were detected in each cell type and compared to human urinary EV isolates (uEV), EV cargo database, kidney biopsy bulk RNA sequencing and proteomics, and single‐cell transcriptomics. This revealed that a high proportion of the in vitro EV signatures were also found in in vivo datasets. Thus, highlighting the robustness of our in vitro model and showing that this approach enables the dissection of cell type specific EV cargo in biofluids and the potential identification of cell‐type specific EV biomarkers of kidney disease.

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Profiling microRNA from nephrectomy and biopsy specimens: predictors of progression and survival in clear cell renal cell carcinoma

Cited by 29 publications

References 31 publications

MicroRNA-30a-5pme: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples

MicroRNA-30a-5pme: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples

Personalisierte Medizin bei Nierenzelltumoren

An in vitro approach to understand contribution of kidney cells to human urinary extracellular vesicles

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