Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer

// Xue Gong 1,2 , Zurab Siprashvili 3 , Okyaz Eminaga 1,4 , Zhewei Shen 2 , Yusuke Sato 5,6 , Haruki Kume 6 , Yukio Homma 6 , Seishi Ogawa 5 , Paul A. Khavari 3 , Jonathan R. Pollack 2 and James D. Brooks 1 1 Department of Urology, School of Medicine, Stanford University, Stanford, California, USA 2 Department of Pathology, School of Medicine, Stanford University, Stanford, California, USA 3 Program in Epithelial Biology, School of Medicine, Stanford University, Stanford, California, USA 4 Department of Urology, University Hospital Cologne, Cologne, Germany 5 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 6 Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Correspondence to: Jonathan R. Pollack, email: // James D. Brooks, email: // Keywords : lincRNA, renal cell carcinoma, kidney cancer, biomarker, prognostication Received : November 04, 2016 Accepted : January 24, 2017 Published : February 24, 2017 Abstract Clear cell renal cell carcinomas (ccRCC) show a broad range of clinical behavior, and prognostic biomarkers are needed to stratify patients for appropriate management. We sought to determine whether long intergenic non-coding RNAs (lincRNAs) might predict patient survival. Candidate prognostic lincRNAs were identified by mining The Cancer Genome Atlas (TCGA) transcriptome (RNA-seq) data on 466 ccRCC cases (randomized into discovery and validation sets) annotated for ~21,000 lncRNAs. A previously uncharacterized lincRNA, SLINKY (Survival-predictive LINcRNA in KidneY cancer), was the top-ranked prognostic lincRNA, and validated in an independent University of Tokyo cohort ( P =0.004). In multivariable analysis, SLINKY expression predicted overall survival independent of tumor stage and grade [TCGA HR=3.5 (CI, 2.2-5.7), P < 0.001; Tokyo HR=8.4 (CI, 1.8-40.2), P = 0.007], and by decision tree, ROC and decision curve analysis, added independent prognostic value. In ccRCC cell lines, SLINKY knockdown reduced cancer cell proliferation (with cell-cycle G 1 arrest) and induced transcriptome changes enriched for cell proliferation and survival processes. Notably, the genes affected by SLINKY knockdown in cell lines were themselves prognostic and correlated with SLINKY expression in the ccRCC patient samples. From a screen for binding partners, we identified direct binding of SLINKY to Heterogeneous Nuclear Ribonucleoprotein K (HNRNPK), whose knockdown recapitulated SLINKY knockdown phenotypes. Thus, SLINKY is a robust prognostic biomarker in ccRCC, where it functions possibly together with HNRNPK in cancer cell proliferation.