epiCaPture: A Urine DNA Methylation Test for Early Detection of Aggressive Prostate Cancer

• Authors: Eve O'Reilly, University College Dublin; Alexandra Tuzova, University College Dublin; Anna L. Walsh, Trinity College Dublin; Niamh M. Russell, University College Dublin; Odharnaith O'Brien, St James Hospital; Sarah Kelly, Trinity College Dublin; Odharna Ni Dhomhnallain, Trinity College Dublin; Liam DeBarra, Trinity College Dublin; Connie M. Dale, Trinity College Dublin; Rick Brugman, Trinity College Dublin; Gavin Clarke, University College Dublin; Olivia Schmidt, University College Dublin; Shane O'Meachair, Trinity College Dublin; Dattatraya Patil, Emory University; Kathryn L. Pellegrini, Emory University; Neil Fleshner, University of Toronto; Julia Garcia, University of Toronto; Fang Zhao, University of Toronto; Stephen Finn, St James Hospital; Robert Mills, Norfolk & Norwich University Hospital; Marcelino Y. Hanna, University of East Anglia; Rachel Hurst, University of East Anglia; Elizabeth McEvoy, Tallaght Hospital; William M. Gallagher, University College Dublin; Rustom P. Manecksha, Trinity College Dublin; Colin S. Cooper, University of East Anglia; Daniel S. Brewer, University of East Anglia; Bharati Bapat, University of Toronto; Martin Sanda, Emory University; Jeremy Clark, University of East Anglia; Antoinette S. Perry, University College Dublin
• Journal Title: JCO PRECISION ONCOLOGY
• Volume: Volume 3
• Publisher: AMER SOC CLINICAL ONCOLOGY | 2019-01-14, Pages 1-18
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1200/PO.18.00134
• Subjects: Health Sciences, Oncology; Biology, Genetics; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; CPG ISLAND HYPERMETHYLATION; PROMOTER METHYLATION; GENE-EXPRESSION; MORTALITY; DIAGNOSIS; BIOPSY; GSTP1; SCORE; PANEL; MEN

Abstract

Purpose Liquid biopsies that noninvasively detect molecular correlates of aggressive prostate cancer (PCa) could be used to triage patients, reducing the burdens of unnecessary invasive prostate biopsy and enabling early detection of high-risk disease. DNA hypermethylation is among the earliest and most frequent aberrations in PCa. We investigated the accuracy of a six-gene DNA methylation panel (Epigenetic Cancer of the Prostate Test in Urine [epiCaPture]) at detecting PCa, high-grade (Gleason score greater than or equal to 8) and high-risk (D'Amico and Cancer of the Prostate Risk Assessment] PCa from urine. Patients and Methods Prognostic utility of epiCaPture genes was first validated in two independent prostate tissue cohorts. epiCaPture was assessed in a multicenter prospective study of 463 men undergoing prostate biopsy. epiCaPture was performed by quantitative methylation-specific polymerase chain reaction in DNA isolated from prebiopsy urine sediments and evaluated by receiver operating characteristic and decision curves (clinical benefit). The epiCaPture score was developed and validated on a two thirds training set to one third test set. Results Higher methylation of epiCaPture genes was significantly associated with increasing aggressiveness in PCa tissues. In urine, area under the receiver operating characteristic curve was 0.64, 0.86, and 0.83 for detecting PCa, high-grade PCa, and highrisk PCa, respectively. Decision curves revealed a net benefit across relevant threshold probabilities. Independent analysis of two epiCaPture genes in the same clinical cohort provided analytical validation. Parallel epiCaPture analysis in urine and matched biopsy cores showed added value of a liquid biopsy. Conclusion epiCaPture is a urine DNA methylation test for high-risk PCa. Its tumor specificity out-performs that of prostate-specific antigen (greater than 3 ng/mL). Used as an adjunct to prostate-specific antigen, epiCaPture could aid patient stratification to determine need for biopsy.