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A urine-based DNA methylation assay, ProCUrE, to identify clinically significant prostate cancer

Zhao, Fang, Olkhov-Mitsel, Ekaterina, Kamdar, Shivani, Jeyapala, Renu, Garcia, Julia, Hurst, Rachel, Hanna, Marcelino Yazbek, Mills, Robert, Tuzova, Alexandra V., O’Reilly, Eve , Kelly, Sarah, Cooper, Colin, Brewer, Daniel, Perry, Antoinette S., Clark, Jeremy, Fleshner, Neil, Bapat, Bharati, Cooper, Colin, Bapat, Bharati, Bristow, Rob, Parker, Chris, Mills, Ian, Pandha, Hardev, Whitaker, Hayley, Neal, David, Olivan, Mireia, Leung, Hing, Perry, Antoinette, Sanda, Martin and Schalken, Jack (2018) A urine-based DNA methylation assay, ProCUrE, to identify clinically significant prostate cancer Clinical Epigenetics, 10, 147. pp. 1-12.

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Abstract

Background Prevention of unnecessary biopsies and overtreatment of indolent disease remains a challenge in the management of prostate cancer. Novel non-invasive tests that can identify clinically significant (intermediate-risk and high-risk) diseases are needed to improve risk stratification and monitoring of prostate cancer patients. Here, we investigated a panel of six DNA methylation biomarkers in urine samples collected post-digital rectal exam from patients undergoing prostate biopsy, for their utility to guide decision making for diagnostic biopsy and early detection of aggressive prostate cancer. Results We recruited 408 patients in risk categories ranging from benign to low-, intermediate-, and high-risk prostate cancer from three international cohorts. Patients were separated into 2/3 training and 1/3 validation cohorts. Methylation biomarkers were analyzed in post-digital rectal exam urinary sediment DNA by quantitative MethyLight assay and investigated for their association with any or aggressive prostate cancers. We developed a Prostate Cancer Urinary Epigenetic (ProCUrE) assay based on an optimal two-gene (HOXD3 and GSTP1) LASSO model, derived from methylation values in the training cohort, and assessed ProCUrE’s diagnostic and prognostic ability for prostate cancer in both the training and validation cohorts. ProCUrE demonstrated improved prostate cancer diagnosis and identification of patients with clinically significant disease in both the training and validation cohorts. Using three different risk stratification criteria (Gleason score, D’Amico criteria, and CAPRA score), we found that the positive predictive value for ProCUrE was higher (59.4–78%) than prostate specific antigen (PSA) (38.2–72.1%) for all risk category comparisons. ProCUrE also demonstrated additive value to PSA in identifying GS ≥ 7 PCa compared to PSA alone (DeLong’s test p = 0.039), as well as additive value to the PCPT risk calculator for identifying any PCa and GS ≥ 7 PCa (DeLong’s test p = 0.011 and 0.022, respectively). Conclusions ProCUrE is a promising non-invasive urinary methylation assay for the early detection and prognostication of prostate cancer. ProCUrE has the potential to supplement PSA testing to identify patients with clinically significant prostate cancer.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Zhao, Fang
Olkhov-Mitsel, Ekaterina
Kamdar, Shivani
Jeyapala, Renu
Garcia, Julia
Hurst, Rachel
Hanna, Marcelino Yazbek
Mills, Robert
Tuzova, Alexandra V.
O’Reilly, Eve
Kelly, Sarah
Cooper, Colin
Brewer, Daniel
Perry, Antoinette S.
Clark, Jeremy
Fleshner, Neil
Bapat, Bharati
Cooper, Colin
Bapat, Bharati
Bristow, Rob
Parker, Chris
Mills, Ian
Pandha, HardevH.Pandha@surrey.ac.uk
Whitaker, Hayley
Neal, David
Olivan, Mireia
Leung, Hing
Perry, Antoinette
Sanda, Martin
Schalken, Jack
Date : 23 November 2018
Funders : Movember
DOI : 10.1186/s13148-018-0575-z
Grant Title : GAP1 Urine Biomarker Award
Copyright Disclaimer : © The Author(s). 2018. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Uncontrolled Keywords : Prostate cancer; PSA; Urine; DNA methylation; Biomarker; Early detection; Overtreatment
Depositing User : Clive Harris
Date Deposited : 29 Jul 2019 09:06
Last Modified : 29 Jul 2019 09:06
URI: http://epubs.surrey.ac.uk/id/eprint/852318

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