Abstract A1-70: Klip1 lincRNA is a prognostic biomarker for clear cell renal cell carcinoma

Abstract

Abstract Background: Large intergenic non-coding RNAs (lincRNAs) are pervasively transcribed in the human genome, and are involved in various biological functions such as cell proliferation, apoptosis and cell signaling pathways. Dysregulation of lincRNAs has been found to underlie human diseases including cancer. As lincRNAs are detectable in blood and urine, they may serve as useful disease biomarkers (as has been shown for PCA3 in prostate cancer). Here, we set out to study lincRNAs in clear cell renal cell carcinoma (ccRCC), the most common tumor of the kidney, accounting for approximately 60,000 cases each year in the United States. In particular, we set out to identify lincRNAs for improved prognostication, in order to better select appropriately aggressive treatments for personalized medicine. Methods and Results: In this study, we mined RNAseq data from The Cancer Genome Atlas (TCGA) on over 500 ccRCC cases. We first re-annotated the TCGA data to identify lincRNAs present from either of two lincRNA compendia. To identify robust prognostic lincRNAs, we split the entire dataset into two even sub-sets and performed survival analysis for each lincRNA in each sub-set. If the P value of the lincRNA was less than 0.001 in both sub-sets, we considered it a candidate “hit”. After 1000 such random sample splits, for each lincRNA we calculated the frequency of “hits”. The top lincRNA, which we named Klip1 (Kidney LincRNA Involved in Proliferation 1) was significant in 90% of random sample splits, which meant its survival prediction power was highly reproduced across the sub-sets of the samples. Klip1 expression correlated with tumor stage, but in multivariate analysis was a significant outcome predictor independent of tumor stage and grade. It was also a significant prognostic marker in an independent Japanese patient cohort (P <0.01). Klip1 expression was cancer specific, and was not detected in the matched normal kidney tissues from the TCGA data. In preliminary functional analyses, siRNA knockdown of Klip1 led to a marked decrease in cancer cell proliferation in three ccRCC cell lines (A498, 786-O and ACHN). By analyzing transcriptomes following Klip1 knockdown, Klip1 does not appear to cis-regulate neighboring genes on the chromosome (as has been shown for some other lincRNAs). However, Klip1 trans-regulated hundreds of genes which are involved in several important cancer related pathways. Discussion and Conclusions: Our findings indicate that lincRNAs have active roles in ccRCC cell proliferation, and may provide useful biomarkers for prognostication, and possibly targets for therapy. Further studies of Klip1 are warranted to translate this biomarker to clinical utility, and to uncover the mechanisms linking Klip1 to cancer cell proliferation. Citation Format: Xue Gong, Jonathan Pollack, James D. Brooks. Klip1 lincRNA is a prognostic biomarker for clear cell renal cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-70.