title: MiR-99b-5p expression and response to tyrosine kinase inhibitor treatment in clear cell renal cell carcinoma patients.
abstract: A number of treatments targeting VEGF or mTOR pathways have been approved for metastatic clear cell Renal Cell Carcinoma (ccRCC), but the majority of patients show disease progression after first line therapy with a very low rate of complete or long-term responders. It has been shown that miRs may play a role in prediction of treatment response in various cancer types. The aim of our study was to identify a miR signature predictive for RCC patients' response to antiangiogenic tyrosine kinase inhibitor (TKI) treatment in the first line therapy. Sequencing of 40 paired normal/tumor formalin fixed and paraffin embedded ccRCC tissues revealed separate clustering via unsupervised dendrograms. With supervised analysis, the strongest differential expression was obtained with miR-99b-5p, which was significantly lower in patients with short progression free survival (<8 months) and TKI non-responders (progressive disease patients according to RECIST) (p<0.0001, each). Validation using RTqPCR and a second patient cohort compiled from three different hospitals (n=65) showed higher expression of miR-99b-5p in complete responders, but this trend did not reach statistical significance. It is concluded that low miR-99b-5p expression analyzed with sequencing methodology may correlate with tumor progression in TKI-treated ccRCC patients.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zürich, Zurich, Switzerland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Lukamowicz-Rajska
authors.affiliation: Institute of Surgical Pathology, University Hospital Zürich, Zurich, Switzerland.
authors.forename: Christiane
authors.initials: C
authors.lastname: Mittmann
authors.affiliation: NEXUS Personalized Health Technologies, ETH Zürich, Zürich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Prummer
authors.affiliation: Institute of Surgical Pathology, University Hospital Zürich, Zurich, Switzerland.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Department of Urology, University Tübingen, Tübingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Bedke
authors.affiliation: Department of Urology, University Tübingen, Tübingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hennenlotter
authors.affiliation: Department of Urology, University Tübingen, Tübingen, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.affiliation: Oncology Department, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Axel
authors.initials: A
authors.lastname: Mischo
authors.affiliation: Oncology Department, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Svenja
authors.initials: S
authors.lastname: Bihr
authors.affiliation: Department of Internal Medicine I, Division of Oncology & Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Schmidinger
authors.affiliation: Department of Internal Medicine I, Division of Oncology & Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Vogl
authors.affiliation: Institute for diagnostic and interventional Radiology, University Hospital Zurich, Zürich, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Blume
authors.affiliation: Institute for diagnostic and interventional Radiology, University Hospital Zurich, Zürich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Karlo
authors.affiliation: Institute of Surgical Pathology, University Hospital Zürich, Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Schraml
authors.affiliation: Institute of Surgical Pathology, University Hospital Zürich, Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000074166:Circulating MicroRNA / Q000097:blood / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D057285:Precision Medicine; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D013557:Switzerland; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000074166:Circulating MicroRNA; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases
keywords: ccRCC; miR; microRNA; renal cancer; sunitinib; treatment response; tyrosine kinase inhibitors