title: Deep sequencing reveals microRNAs predictive of antiangiogenic drug response.
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 (Pvalues from 6 × 10-9to 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 × 10-8and 7.8 × 10-7for 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.
authors.affiliation: Oncology Unit, HM Hospitales - Centro Integral Oncológico HM Clara Campal, Madrid, Spain.|Spanish Oncology Genitourinary Group, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Donas
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, and.|Laboratory for Experimental Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Beuselinck
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.affiliation: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, and.|Laboratory for Experimental Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.affiliation: Laboratory for Experimental Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, and.|Laboratory for Experimental Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bechter
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Apellániz-Ruiz
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Luis Javier
authors.initials: LJ
authors.lastname: Leandro-García
authors.affiliation: Spanish Oncology Genitourinary Group, Madrid, Spain.|Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Esteban
authors.affiliation: Spanish Oncology Genitourinary Group, Madrid, Spain.|Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Castellano
authors.affiliation: Spanish Oncology Genitourinary Group, Madrid, Spain.|Hospital Universitario Son Espases, Palma de Mallorca, Spain.
authors.forename: Aranzazu
authors.initials: A
authors.lastname: González Del Alba
authors.affiliation: Spanish Oncology Genitourinary Group, Madrid, Spain.|Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Climent
authors.affiliation: Spanish Oncology Genitourinary Group, Madrid, Spain.|Hospital Universitario Fundación Alcorcón, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Hernando
authors.affiliation: Spanish Oncology Genitourinary Group, Madrid, Spain.|Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: José Angel
authors.initials: JA
authors.lastname: Arranz
authors.affiliation: Tumour Bank Unit, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Morente
authors.affiliation: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodriguez-Antona
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015996:Survival Rate
chemical_list: D020533:Angiogenesis Inhibitors; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors