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 G1 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.
Highlights
In the United States, kidney cancer is the 6th and 10th most common cancer diagnosed in men and women, respectively [1]
We have identified SLINKY as a potentially significant lincRNA in clear cell renal cell carcinoma (ccRCC) biology that could serve as an important biomarker of ccRCC prognosis
Elevated expression of SLINKY was a strong predictor of worse overall survival in the The Cancer Genome Atlas (TCGA) cohort, and validated in a smaller set of ccRCCs in an ethnically distinct cohort of patients from Japan
Summary
In the United States, kidney cancer is the 6th and 10th most common cancer diagnosed in men and women, respectively [1]. Conventional or clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype, with nearly 60,000 cases diagnosed per year, and accounting for 14,000 yearly deaths. Once a mass is identified, diagnosis usually comes after surgical removal of the mass or the kidney, or with transcutaneous needle biopsies, which are limited in value because of their small size and the heterogeneous nature of many renal tumors that can confound definitive diagnosis. Even in cases where the masses are malignant, many small ccRCCs can show an indolent course and be effectively managed with active surveillance, in elderly patients or patients with co-morbidities where risks of surgery might outweigh the potential mortality benefit of tumor resection. Identification of molecular pathways involved in ccRCC progression and death could provide novel insights into ccRCC biology
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