Despite biomarker development advances, early detection of aggressive prostate cancer (PCa) remains challenging. We previously developed a clinical-grade urine test (Michigan Prostate Score [MiPS]) for individualized aggressive PCa risk prediction.
MiPS combines serum prostate-specific antigen (PSA), the TMPRSS2:ERG (T2:ERG) gene fusion, and PCA3 lncRNA in whole urine after digital rectal examination (DRE).
To improve on MiPS with a novel next-generation sequencing (NGS) multibiomarker urine assay for early detection of aggressive PCa.
Preclinical development and validation of a post-DRE urine RNA NGS assay (Urine Prostate Seq [UPSeq]) assessing 84 PCa transcriptomic biomarkers, including T2:ERG, PCA3, additional PCa fusions/isoforms, mRNAs, lncRNAs, and expressed mutations. Our UPSeq model was trained on 73 patients and validated on a held-out set of 36 patients representing the spectrum of disease (benign to grade group [GG] 5 PCa).
The area under the receiver operating characteristic curve (AUC) of UPSeq was compared with PSA, MiPS, and other existing models/biomarkers for predicting GG ≥3 PCa.
UPSeq demonstrated high analytical accuracy and concordance with MiPS, and was able to detect expressed germline HOXB13 and somatic SPOP mutations. In an extreme design cohort (n = 109; benign/GG 1 vs GG ≥3 PCa, stratified to exclude GG 2 cancer in order to capture signal difference between extreme ends of disease), UPSeq showed differential expression for T2:ERG.T1E4 (1.2 vs 78.8 median normalized reads, p < 0.00001) and PCA3 (1024 vs 2521, p = 0.02), additional T2:ERG splice isoforms, and other candidate biomarkers. Using machine learning, we developed a 15-transcript model on the training set (n = 73) that outperformed serum PSA and sequencing-derived MiPS in predicting GG ≥3 PCa in the held-out validation set (n = 36; AUC 0.82 vs 0.69 and 0.69, respectively).
These results support the potential utility of our novel urine-based RNA NGS assay to supplement PSA for improved early detection of aggressive PCa.
We have developed a new urine-based test for the detection of aggressive prostate cancer, which promises improvement upon current biomarker tests.
European urology oncology. 2021 Mar 31 [Epub ahead of print]
Andi K Cani, Kevin Hu, Chia-Jen Liu, Javed Siddiqui, Yingye Zheng, Sumin Han, Srinivas Nallandhighal, Daniel H Hovelson, Lanbo Xiao, Trinh Pham, Nicholas W Eyrich, Heng Zheng, Randy Vince, Jeffrey J Tosoian, Ganesh S Palapattu, Todd M Morgan, John T Wei, Aaron M Udager, Arul M Chinnaiyan, Scott A Tomlins, Simpa S Salami
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA., Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA., Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA., Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: ., Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: .