Urinary miRNAs Predict Metastasis in Patients With Clinically Localized Clear Cell Renal Cell Carcinoma Treated With Nephrectomy

Rodolfo Borges Dos Reis; Xiang Shu; Yuanqing Ye; Leonardo Borregales; Jose A Karam; Mehad Adibi; Xifeng Wu; Leonardo O Reis; Christopher G Wood

doi:10.1016/j.clgc.2023.10.003

Urinary miRNAs Predict Metastasis in Patients With Clinically Localized Clear Cell Renal Cell Carcinoma Treated With Nephrectomy

Clin Genitourin Cancer. 2024 Feb;22(1):e156-e162.e4. doi: 10.1016/j.clgc.2023.10.003. Epub 2023 Oct 6.

Authors

Rodolfo Borges Dos Reis¹, Xiang Shu², Yuanqing Ye², Leonardo Borregales³, Jose A Karam³, Mehad Adibi³, Xifeng Wu², Leonardo O Reis⁴, Christopher G Wood³

Affiliations

¹ Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirao Preto, Sao Paulo, Brazil.
² Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
³ Department of Urology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
⁴ UroScience, State University of Campinas, Unicamp, and Pontifical Catholic University of Campinas, PUC-Campinas, Campinas, Sao Paulo, Brazil. Electronic address: reisleo.l@gmail.com.

PMID: 37945405
DOI: 10.1016/j.clgc.2023.10.003

Abstract

Purpose: Patients with clear cell renal cell carcinoma (ccRCC) might develop metastasis after surgery with curative intent. We aimed to characterize the expression levels of microRNAs in the urine (UmiRNAs) of patients before and after nephrectomy to determine the impact of UmiRNAs expression in the emergence of metastases.

Methods: We prospectively collected pre- and post-nephrectomy urine samples from 117 patients with clinically localized and locally advanced ccRCC. UmiRNAs were extracted, purified, and measured using RT-PCR. Relative quantifications (RQ) of 137 UmiRNAs were calculated through 2^-∆∆ method. The post-surgery/pre-surgery RQs ratio represented the magnitude of the expression levels of the UmiRNAs. The association of UmiRNA expression and the development of distant metastases was tested with Cox regression model.

Results: Five UmiRNAs (miR-191-5p, miR-324-3p, miR-186-5p, miR-93-5p, miR-30b-5p) levels were upregulated before nephrectomy (p < .05). This conferred a 2- to 4-fold increased risk of metastasis, with miR-191-5p showing the most significant association with this endpoint (HR = 4.16, 95% CI = 1.38-12.58, p = .011). In a multivariate model stratified with stage and Fuhrman grade, we found that miR-191-5p, miR-324-3p, and miR-186-5p exhibited a strong association with metastasis development in patients with pathological T3 (pT3) tumors. Enrichment analysis with the most differentially expressed UmiRNAs showed that these UmiRNAs targeted genes that regulate cell survival and proliferation.

Conclusion: Our study indicated UmiR-191-5p, UmiR-324-3p, and UmiR-186-5p are potential markers to predict the development of metastasis, particularly in pT3 patients.

Patient summary: We compared changes of UmiRNAs expression detected pre- and postnephrectomy of patients with ccRCC. Our findings suggest that UmiRNA expression likely reflects tumor-specific changes that can be promising to predict the metastasis development, particularly in patients with non-metastatic locally advanced ccRCC. If confirmed, these findings may be useful for surveillance protocols for adjuvant therapy protocols.

Keywords: Biomarker; Kidney Cancer; Liquid biopsy; MicroRNA; Urinary MicroRNA.

MeSH terms

Biomarkers, Tumor / genetics
Carcinoma* / genetics
Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / pathology
Carcinoma, Renal Cell* / surgery
Gene Expression Regulation, Neoplastic
Humans
Kidney Neoplasms* / genetics
Kidney Neoplasms* / pathology
Kidney Neoplasms* / surgery
MicroRNAs* / genetics
Nephrectomy
Proportional Hazards Models

Substances

MicroRNAs
Biomarkers, Tumor
MIRN186 microRNA, human
MIRN324 microRNA, human