Investigating the long noncoding RNA SChLAP1 as a prognostic tissue and urine biomarker in prostate cancer

7 Background: Improved prognostic biomarkers are needed for localized prostate cancer. We undertook an unbiased large-scale analysis of genes associated with metastatic progression and validated the prognostic ability of the top candidate gene. Methods: Prostate cancer samples from prostatectomy patients were analyzed for gene expression using a clinical-grade, high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci and assessed in a CLIA-certified laboratory. Nomination of prognostic candidate genes was performed on a discovery cohort (n=545) and validated on 3 independent cohorts (n=463). Multivariate analyses were performed for the primary endpoint of metastasis. The top prostate-specific gene was further evaluated in 208 additional tumor samples with a novel RNA in-situ hybridization (ISH) assay and in urine samples from 230 patients using PCR. Results: Of all known genes, the long noncoding RNA SChLAP1 ranked first for elevated expression in patients with metastatic progression by receiver-operator-curve analyses. Validation in three independent cohorts confirmed the prognostic value of SChLAP1. On multivariate modeling, SChLAP1 expression independently predicted metastasis within 10 years (odds ratio (OR) = 2.45, 95% confidence interval (CI) 1.70 – 3.53), death within 10 years (OR = 1.93, 95% CI 1.31 – 2.85), and biochemical recurrence within 5 years (OR = 1.76, 95% CI 1.28 – 2.41) with ORs comparable to Gleason score. Evaluation of SChLAP1 expression by RNA ISH confirmed a significant association with disease recurrence (OR = 1.99, 95% CI 1.06 – 3.73). Evaluation of urine SChLAP1 levels demonstrated increased expression in patients at higher risk for disease progression. Conclusions: We perform the largest high-throughput, unbiased study of prostate cancer prognostic biomarkers to date and discover SChLAP1 as a top gene predictive of metastatic progression. We validate SChLAP1 extensively with a clinical-grade assay. We show feasibility of a RNA ISH assay and a non-invasive urine test for SChLAP1. Our results, spanning 1,446 patients from 6 independent patient cohorts, suggest that SChLAP1 represents a very promising biomarker for aggressive clinical course.