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JCI Insight. 2016 Jul 7;1(10):e86051. doi: 10.1172/jci.insight.86051.

Deep sequencing reveals microRNAs predictive of antiangiogenic drug response.

Author information

1
Oncology Unit, HM Hospitales - Centro Integral Oncológico HM Clara Campal, Madrid, Spain.
2
Spanish Oncology Genitourinary Group, Madrid, Spain.
3
Department of General Medical Oncology, University Hospitals Leuven, and.
4
Laboratory for Experimental Oncology, KU Leuven, Leuven, Belgium.
5
Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
6
Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
7
Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain.
8
Hospital Universitario Central de Asturias, Oviedo, Spain.
9
Hospital Universitario 12 de Octubre, Madrid, Spain.
10
Hospital Universitario Son Espases, Palma de Mallorca, Spain.
11
Fundación Instituto Valenciano de Oncología, Valencia, Spain.
12
Hospital Universitario Fundación Alcorcón, Madrid, Spain.
13
Hospital General Universitario Gregorio Marañón, Madrid, Spain.
14
Tumour Bank Unit, Spanish National Cancer Research Centre, Madrid, Spain.

Abstract

The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 × 10-9 to 3 × 10-3). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR-1307-3p, miR-155-5p, and miR-221-3p (P = 4.6 × 10-3, 6.5 × 10-3, and 3.4 × 10-2, respectively). Furthermore, a 2 miRNA-based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64-0.85; P = 1.3 × 10-4) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (P = 6.8 × 10-8 and 7.8 × 10-7 for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment.

PMID:
27699216
PMCID:
PMC5033860
DOI:
10.1172/jci.insight.86051
[Indexed for MEDLINE]
Free PMC Article

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