Oncotarget

Research Papers:

Prognostic microRNAs in upper tract urothelial carcinoma: multicenter and international validation study

Laura Izquierdo _, Ruth Montalbo, Mercedes Ingelmo-Torres, Carme Mallofré, Miguel Ramírez-Backhaus, Jose Rubio, Antoine Van der Heijden, Ewout Schaafsma, Antonio Lopez-Beltran, Ana Blanca, Nathan Lawrentschuk, Antonio Alcaraz and Lourdes Mengual

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Oncotarget. 2017; 8:51522-51529. https://doi.org/10.18632/oncotarget.17884

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Abstract

Laura Izquierdo1,2,*, Ruth Montalbo1,2,*, Mercedes Ingelmo-Torres1,2, Carme Mallofré3, Miguel Ramírez-Backhaus4, Jose Rubio4, Antoine G. Van der Heijden5, Ewout Schaafsma6, Antonio Lopez-Beltran7, Ana Blanca8, Nathan Lawrentschuk9, Antonio Alcaraz1,2 and Lourdes Mengual1,2

1Department of Urology, Hospital Clinic, IDIBAPS, Barcelona, Spain

2Laboratory of Urology, Hospital Clinic, IDIBAPS, Barcelona, Spain

3Department of Pathology, Hospital Clinic, Barcelona, Spain

4Department of Urology of Fundación IVO, Valencia, Spain

5Department of Urology, Radboud University Centre, Nijmegen, Netherlands

6Department of Pathology, Radboud University Centre, Nijmegen, Netherlands

7Department of Pathology of Reina Sofía Hospital and Maimonides Biochemical Research Institute, Córdoba, Spain

8Department of Urology, Maimonides Biochemical Research Institute of Córdoba, Córdoba, Spain

9Department of Urology, University of Melbourne, Department of Surgery/Olivia Newton-John Cancer Research Institute, Melbourne, Australia

*These authors have contributed equally to this work

Correspondence to:

Laura Izquierdo, email: lizquier@clinic.cat

Keywords: microRNAs, prognosis, upper tract urothelial carcinoma

Abbreviations: UTUC, upper urinary tract tumor; RNU, radical nephroureterectomy

Received: November 25, 2016    Accepted: April 26, 2017    Published: May 16, 2017

ABSTRACT

Objective: To validate previously discovered miRNAs (miR-31-5p and miR-149-5p) as prognostic factors for UTUC in an independent cohort of UTUC patients.

Patients and Methods: Multicenter, international and retrospective study of formalin-fixed paraffin-embedded tissue samples from 103 UTUC patients (45 progressing and 58 non-progressing) who underwent radical nephroureterectomy. Total RNA was isolated and reverse transcribed. The expression of target miRNAs (miR-31-5p and miR-149-5p) and the endogenous control miR-218-5p was evaluated in all samples by reverse transcription quantitative PCR. Normalized miRNA expression values were evaluated by multivariate forward stepwise Cox regression analysis. Kaplan Meier curves were used to discriminate between two groups of patients with a different probability of tumour progression.

Results: The mean age (range) of the series was 67 (33-94) years. Overall, 45 patients (43.7%) developed tumour progression and 32 patients (31.2%) died, 20 of these (62.5%) due to their UTUC, after a median follow-up of 36 months. The mean time for tumour progression and cancer-specific survival were 15 and 20 months, respectively. Five year tumour progression free survival and cancer-specific survival were 58% for ≤ pT2, 36% for pT3 and 0% for pT4 and 67.8% for ≤ pT2, 50.6% for pT3 and 0% for pT4, respectively. In the multivariate analysis, expression of miR-31-5p was found to be an independent prognostic factor of tumour progression (HR 1.1; 95% CI 1.039-1.273; p=0.02). Kaplan Meier curve shows that miR-31-5p expression values are able to discriminate between two groups of UTUC patients with a different probability of tumour progression (p=0.007).

Conclusions: We have been able to validate our previous results in an independent multicentre international cohort of UTUC patients, suggesting that miRNA-31-5p could be a useful prognostic marker of UTUC progression. The application of miRNA expression values to clinical practice could refine the currently used clinicopathological-based approach for predicting UTUC patients’ outcome.


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