ORIGINAL ARTICLE – UROLOGIC ONCOLOGY 4-miRNA Score Predicts the Individual Metastatic Risk of Renal Cell Carcinoma Patients Joana Heinzelmann, PhD 1,2 , Madeleine Arndt 1 , Ramona Pleyers, MD 1 , Tobias Fehlmann 3 , Sebastian Hoelters, PhD 1,9 , Philip Zeuschner, MD 1 , Alexander Vogt 1 , Alexey Pryalukhin, MD 4,10 , Elke Schaeffeler, PhD 5,6 , Rainer M. Bohle, MD, PhD 4 , Mieczyslaw Gajda, MD 7 , Martin Janssen, MD 1 , Michael Stoeckle, MD, PhD 1 , and Kerstin Junker, MD, PhD 1,8 1 Department of Urology and Pediatric Urology, Saarland University, Homburg, Saar, Germany; 2 Department of Ophthalmology, Martin-Luther University Halle-Wittenberg, University Hospital Halle (Saale), Halle (Saale), Germany; 3 Department of Clinical Bioinformatics, Saarland University, Saarbruecken, Germany; 4 Institute of Pathology, Saarland University, Homburg, Saar, Germany; 5 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; 6 University of Tuebingen, Tuebingen, Germany; 7 Institute of Pathology, Jena University Hospital, Jena, Germany; 8 Department of Urology, Jena University Hospital, Jena, Germany; 9 Present Address: SERVA Electrophoresis GmbH, Heidelberg, Germany; 10 Present Address: Institute of Pathology, Bonn University Medical School, Bonn, Germany ABSTRACT Background. In order to improve individual prognostica- tion as well as stratification for adjuvant therapy in patients with clinically localized clear cell renal cell carcinoma (ccRCC), reliable prognostic biomarkers are urgently needed. In this study, microRNAs (miRNAs) have emerged as promising candidates. We investigated whether a com- bination of differently expressed miRNAs in primary tumors can predict the individual metastatic risk. Methods. Using two prospectively collected biobanks of academic centers, 108 ccRCCs were selected, including 57 from patients with metastatic disease at diagnosis or during follow-up and 51 without evidence of metastases. Fourteen previously identified candidate miRNAs were tested in 20 representative formalin-fixed and paraffin embedded sam- ples in order to select the best discriminators between metastatic and nonmetastatic ccRCC. These miRNAs were approved in 108 tumor samples. We evaluated the association of altered miRNA expression with the meta- static potential of tumors using quantitative polymerase chain reaction. A prognostic 4-miRNA model has been established using a random forest classifier. Cox regression analyses were performed for correlation of the miRNA model and clinicopathological parameters to metastasis- free and overall survival. Results. Nine miRNAs indicated significant expression alterations in the small cohort. These miRNAs were vali- dated in the whole cohort. The established 4-miRNA score (miR-30a-3p/-30c-5p/-139-5p/-144-5p) has been identified as a superior predictor for metastasis-free survival (hazard ratio 12.402; p = 7.0E-05) and overall survival (p = 1.1E-04) compared with clinicopathological param- eters, and likewise in the Leibovich score subgroups. Conclusions. We identified a 4-miRNA model that was found to be superior to clinicopathological parameters in accurately predicting individual metastatic risk and can support patient selection for risk-stratified follow-up and adjuvant therapy studies. Clear cell renal cell carcinoma (ccRCC) remains the most common renal cell carcinoma (RCC) subtype, rep- resenting 75–80% of all cases. 1 The prognosis of ccRCC strongly depends on the development of distant metastases. Approximately 20% of patients experience metastatic dis- ease at the time of initial diagnosis (synchronous Electronic supplementary material The online version of this article (https://doi.org/10.1245/s10434-019-07578-3) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2019 First Received: 10 January 2019 K. Junker, MD, PhD e-mail: kerstin.junker@uks.eu Ann Surg Oncol https://doi.org/10.1245/s10434-019-07578-3