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Clinical Studies

A prognostic microRNA-based signature for localized clear cell renal cell carcinoma: the Bio-miR study

British Journal of Cancer (2025)Cite this article

Subjects

Abstract

Background

Two thirds of renal cell carcinoma (RCC) patients have localized disease at diagnosis. A significant proportion of these patients will relapse. There is a need for prognostic biomarkers to improve risk-stratification and specific treatments for patients that relapse. The objective of this study is to determine the clinical utility of microRNA signatures as prognostic biomarkers in localized clear cell RCC (ccRCC) and propose new therapeutic targets in patients with a high-risk of relapse.

Patients and methods

The microRNA profiles from a discovery cohort of 71 T1-T2 ccRCC patients (n = 88) were analyzed using microarrays. MicroRNAs prognostic value was established, and a microRNAs signature predicting relapse for T1b-T3 disease was defined. Independent validation was carried out by qPCR in cohorts from UK (n = 75) and Spain (n = 180), and the TCGA cohort (n = 175). In the Spanish validation cohort, proteomics experiments were done. Proteins were extracted from FFPE tissue and analyzed using by data-independent acquisition mass spectrometry. Additionally, ccRCC TCGA RNA-seq data was also analyzed. Both protein and RNA-seq data was analyzed using Significance Analysis of Micorarrays (SAM) and probabilistic graphical models, which allow the identification of relevant biological processes between low and high-risk tumors.

Results

A 9-microRNAs signature, Bio-miR, classified patients into low- and high-risk with disease-free survival (DFS) at 5 years of 87.12 vs. 54.17% respectively (p = 0.0086, HR = 3.58, 95%CI: 1.37-8.3). Results were confirmed in the validation cohorts with 5-year DFS rates of 94% vs. 62% in the UK cohort (HR = 7.14, p = 0.001), 82.9% vs. 58.7% in the Spanish cohort (HR = 2.46, p = 0.0013), and 5-year overall survival rates of 72.7% vs. 44.5% in the TCGA cohort (HR = 2.43, p = 0.0012). Among low-risk patients according to adjuvant immunotherapy clinical trial criteria, Bio-miR identified a high-risk group. Maybe those patients ought to be considered to receive adjuvant therapy. Proteins overexpressed in the high-risk group were mainly related to focal adhesion, serine and inositol metabolism, and angiogenesis. Probabilistic graphical models defined eight functional nodes related to specific biological processes. Differences between low- and high-risk tumors were detected in complement activation and translation functional nodes. In ccRCC TCGA cohort, 676 genes were differentially expressed between low and high-risk patients, mainly related to complement activation, adhesion, and chemokine and cytokine cascades. In this case, probabilistic graphical models defined ten functional nodes. Calcium binding, membrane, adhesion, extracellular matrix, blood microparticle, inflammatory response and immune response had higher functional node activity, and metabolism node, containing genes related to retinol and xenobiotic and CYP450 metabolism, had lower activity in the high-risk group.

Conclusions

Bio-miR dichotomizes ccRCC patients with non-metastatic disease into those with low- and high-risk of relapse. This has implications for treatment and follow-up, identifying patients most likely to benefit from adjuvant treatment in clinical trials, preventing unnecessary exposure to side-effects, and providing health economics benefits. Additionally, promising therapeutic targets, as angiogenesis, immune response, metabolism, or complement activation, were found deregulated in high-risk ccRCC patients defined by Bio-miR. These findings may be useful to select patients for tailored, molecularly-driven clinical trials.

Patient summary

Identifying which patients with kidney cancer are most at risk of their cancer coming back after surgery is critical, so that they can be prioritized for early treatment. We have identified a combination of biomarkers present in the cancer tissue (called BiomiR) which can help to do this.

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Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5: Disease-free survival in Bio-miR Spanish validation cohort according to eligibility to receive pembrolizumab as per KN564 criteria.
Fig. 6: Differential expressed proteins between Bio-miR low and high-risk ccRCC patients from the Spanish BiomiR validation cohort.
Fig. 7: Systems Biology analyses in ccRCC Spanish Bio-miR validation cohort.
Fig. 8: Differential gene expression between Bio-miR low and high-risk patients in ccRCC TCGA cohort.
Fig. 9: Systems Biology analysis of ccRCC TCGA cohort.

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Data availability

Proteomics raw data are available in the ProteomeXchange Consortium via the PRIDE (http://www.ebi.ac.uk/pride) partner repository with the data set identifier PXD039258.

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Acknowledgements

We want acknowledge the Biobank of Hospital La Paz, Basque Biobank for Research O + EHUN, and the SSPA Biobank, integrated in the Spanish National Biobanks Network for their collaboration. We want to particularly acknowledge the patients who participated in this study.

Funding

This work was supported by EPIC-XS, project number 823839, funded by the Horizon 2020 programme of the European Union. CDTI IDI-20200073, PTQ2018-009760 (MICINN), EPIC-XS, project number 823839, funded by the Horizon 2020 programme of the European Union.

Author information

Author notes

  1. These authors contributed equally: Álvaro Pinto-Marín, Lucía Trilla-Fuertes.

Authors and Affiliations

  1. Medical Oncology Service, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain

    Álvaro Pinto-Marín, Jesús Miranda Poma, Ana Pertejo & Enrique Espinosa

  2. Molecular Oncology Lab, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain

    Lucía Trilla-Fuertes, Rocío López-Vacas, Juan Ángel Fresno Vara & Angelo Gámez-Pozo

  3. Leeds Institute of Medical Research at St James’s, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK

    Naveen S. Vasudev, Michelle Wilson, Joanne Brown & Rosamonde E. Banks

  4. Department of Pathology, University Hospital La Paz, IDIPAZ, UAM, Madrid, Spain

    Eugenia García-Fernández & Pilar González-Peramato

  5. Urology Service, Hospital Universitario 12 de Octubre, Madrid, Spain

    Natalia Miranda

  6. Biomedica Molecular Medicine SL, Madrid, Spain

    Elena López-Camacho, Andrea Zapater-Moros & Angelo Gámez-Pozo

  7. Proteomics Group, Functional Genomics Center Zurich, Zurich, Switzerland

    Antje Dittmann & Laura Kunz

  8. IdiPAZ Biobank, La Paz University Hospital-IdiPAZ, Madrid, Spain

    Yaiza Pedroche-Just

  9. Medical Oncology Service, Hospital Universitario 12 de Octubre, Madrid, Spain

    Guillermo de Velasco & Daniel Castellano

  10. Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain

    Enrique Espinosa & Juan Ángel Fresno Vara

Authors
  1. Álvaro Pinto-Marín
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  2. Lucía Trilla-Fuertes
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  3. Jesús Miranda Poma
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  4. Naveen S. Vasudev
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  5. Eugenia García-Fernández
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  6. Rocío López-Vacas
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  7. Natalia Miranda
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  8. Michelle Wilson
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  9. Elena López-Camacho
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  10. Ana Pertejo
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  11. Antje Dittmann
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  12. Laura Kunz
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  13. Joanne Brown
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  14. Yaiza Pedroche-Just
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  15. Andrea Zapater-Moros
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  16. Guillermo de Velasco
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  17. Daniel Castellano
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  18. Pilar González-Peramato
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  19. Enrique Espinosa
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  20. Rosamonde E. Banks
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  21. Juan Ángel Fresno Vara
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  22. Angelo Gámez-Pozo
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Contributions

AP-M, JM-P, NSV, NM, AP, GdV, DC, and EE participated in data curation. NV, EG-F, RL-V, MW, EL-C, AD, LK, JB, YP-J, PG-P, and REB contributed to methodology. LT-F, NSV, MW, EL-C, AZ-M, JAFV, and AG-P performed formal analysis. AP-M and LT-F wrote the original draft. AG-P reviewed and corrected the manuscript. AP-M, EE, JAFV and AG-P participated in the conceptualization and design of the study. AG-P obtained resources for doing this study.

Corresponding authors

Correspondence to Álvaro Pinto-Marín or Angelo Gámez-Pozo.

Ethics declarations

Competing interests

AP: Research funding: Pfizer, BMS Advisory boards: Pfizer, Novartis, Ipsen, BMS, Janssen, Astellas, Sanofi, Bayer, Clovis, Roche, MSD, Pierre Fabre, Merck Clinical trial payments: Pfizer, Bayer, Janssen, MSD, Clovis, Pharmacyclics, BMS, Sanofi, Astra Zeneca, Roche, Eisai, Aveo. Travel arrangements: Janssen, Roche, Pfizer, BMS, Ipsen. EE: Biomedica Molecular Medicine Shares, Bio-miR patent, Courses: BMS, MSD, Pierre Fabré and Novartis. AGP: Biomedica Molecular Medicine Shares, Bio-miR patent. JAFV: Biomedica Molecular Medicine Shares, Bio-miR patent. NV: Research funding: BMS Advisory boards: BMS, Pfizer, Merck Speaker fees: Ipsen, BMS, Eisai, EUSA pharma.

Ethical approval and consent to participate

In all cases, written informed consent was obtained from patients and ethical approvals were obtained, specifically Hospital Doce de Octubre Ethical Committee (17/214) for the discovery cohort, Leeds East Research Ethics Committee (20/YH/0103) for the Leeds validation cohort and Hospital La Paz Ethical Committee (PI-3310) for the Spanish validation cohort. All methods were performed in accordance with the relevant guidelines and regulations.

Additional information

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Supplementary information

Supplementary files

41416_2025_3008_MOESM2_ESM.txt

List pf proteins overexpressed in BiomiR high-risk group in the Spanish validation cohort according to a Significance Analysis of Microarrays and their gene ontology

41416_2025_3008_MOESM3_ESM.txt

Functional nodes identified in the protein network built using probabilistic graphical models and proteomics data from the Spanish validation cohort

41416_2025_3008_MOESM4_ESM.txt

List of proteins overexpressed in BiomiR high-risk group in the ccRCC TCGA cohort according to a Significance Analysis of Microarrays and their gene ontology

41416_2025_3008_MOESM5_ESM.txt

Functional nodes identified in the protein network built using probabilistic graphical models and proteomics data from the ccRCC TCGA cohort

Sup.tab13

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Pinto-Marín, Á., Trilla-Fuertes, L., Miranda Poma, J. et al. A prognostic microRNA-based signature for localized clear cell renal cell carcinoma: the Bio-miR study. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03008-2

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  • DOI: https://doi.org/10.1038/s41416-025-03008-2

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