New urine-based test holds promise for detecting aggressive prostate cancer

Using next-generation RNA sequencing, the UPSeq test assesses 15 biomarkers to find aggressive prostate cancer that can be missed by biopsies or imaging tests.

prostate cancer cells in blue green and orange in a microscope view with badge on bottom right saying lab note in yellow and navy blue

Castration resistant prostate cancer, human tissue. Mateus Crespo, The Institute of Cancer Research (CC BY 4.0)

Researchers at the University of Michigan Rogel Cancer Center have developed a new urine-based, multi-biomarker test to detect aggressive prostate cancer that performed better than existing biomarker tests in initial preclinical evaluations.

The Urine Prostate Seq test, or UPSeq for short, uses next-generation genomic sequencing to analyze urine collected from men following a digital rectal exam.

The team used machine learning, a form of artificial intelligence, to zero in on 15 RNA transcripts that together create a “liquid biopsy” that outperformed the standard prostate-specific antigen blood test alone, a previous test developed at U-M called Michigan Prostate Score (MiPS) and several other existing biomarker tests, according to findings published in European Urology Oncology.

If a man is found to have an elevated PSA level, doctors first need to determine whether it’s a sign of prostate cancer, and if it is cancer, whether that cancer is aggressive.

“The problem is that a patient can have multiple areas of cancer in the prostate and these areas may be different than each other,” explains senior study author Simpa Salami, M.D., M.P.H., an assistant professor of urology at Michigan Medicine. “Because of this, both prostate biopsies and MRI scans can miss evidence of aggressive disease. So, this urine test is designed to tell us what’s really happening throughout the whole prostate.”

Workflow for the development of urine RNA NGS assay (UPSeq) for early detection of aggressive prostate cancer (PCa)

Fig. 1

Our previously validated FFPE tissue-based PCa prognostic RNA NGS assay served as the starting pool of gene targets and amplicons. Its 306 amplicons include those in the three commercial tissue-based prognostic assays, relevant transcriptional signatures, vast majority of PCa gene fusions, known and novel PCa-related lncRNAs, expressed somatic/germline variants, etc. Heatmap shows tissue expression data with expected patterns of expression across the disease spectrum. We filtered these 306 targets to select 84 transcripts relevant in urine, by prioritizing (1) prostate-specific targets (FOLH1 expression levels by tissue type in GTEX are shown), (2) transcripts differentially expressed in PCa versus normal prostate tissue (HPN tissue expression levels for benign vs prostate cancer are shown), and (3) transcripts differentially expressed in aggressive PCa (grade group >1; SChLAP1 tissue expression levels for benign vs PCa are shown ). For our urine assay, ~30 ml of first-catch urine obtained immediately after a digital rectal examination of the prostate is mixed with RNA-preserving Hologic urine transport media in a 1:1 ratio. Five milliliters of this mix are used for RNA isolation. NGS with the 84-transcript panel described above is performed on the Ion Torrent sequencing platform, and target transcript read counts are normalized to sample-specific KLK3 read counts. A machine learning approach was used to train a model for predicting the presence of PCa and aggressive PCa. CRPC = castration-resistant prostate cancer; FFPE = formalin-fixed paraffin embedded; GG = grade group; NGS = next-generation sequencing; UPSeq = Urine Prostate Seq.

The research team believes the test has several potential clinical applications, including early detection of aggressive cancer in men at the time of an initial biopsy, and ruling out aggressive disease in men considering active surveillance — which involves monitoring their cancer through regular physical exams, blood tests, biopsies and imaging tests, and delaying treatment until the cancer shows signs of worsening.

“A novel aspect of this test is that it can detect inheritable mutations in the HOXB13 gene that could warn us that the patient’s family members may also be at higher risk for prostate cancer,” Salami adds.

The researchers plan to continue to develop and validate the test in additional patients, the authors note.

SourceUniversity of Michigan Health

Cani AK, Hu K, Liu CJ, Siddiqui J, Zheng Y, Han S, Nallandhighal S, Hovelson DH, Xiao L, Pham T, Eyrich NW, Zheng H, Vince R Jr, Tosoian JJ, Palapattu GS, Morgan TM, Wei JT, Udager AM, Chinnaiyan AM, Tomlins SA, Salami SS. (2021) Development of a Whole-urine, Multiplexed, Next-generation RNA-sequencing Assay for Early Detection of Aggressive Prostate Cancer. Eur Urol Oncol [Eub ahead of print]. [article]

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