Fang Zhao1, Ekaterina Olkhov-Mitsel1, Theodorus van der Kwast2, Jenna Sykes3, Darko Zdravic4, Vasundara Venkateswaran5, Alexandre R Zlotta6, Andrew Loblaw7, Neil E Fleshner8, Laurence Klotz5, Danny Vesprini7, Bharati Bapat9. 1. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology, University Health Network, Toronto, Ontario, Canada. 3. St. Michael's Hospital, Toronto, Ontario, Canada. 4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 5. Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. 6. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Department of Urology and Surgical Oncology, University Health Network, Toronto, Ontario, Canada. 7. Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. 8. Department of Urology and Surgical Oncology, University Health Network, Toronto, Ontario, Canada. 9. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology, University Health Network, Toronto, Ontario, Canada. Electronic address: bapat@lunenfeld.ca.
Abstract
PURPOSE: Patients with prostate cancer on active surveillance are monitored by repeat prostate specific antigen measurements, digital rectal examinations and prostate biopsies. A subset of patients on active surveillance will later reclassify with disease progression, prompting definitive treatment. To minimize the risk of under treating such patients on active surveillance minimally invasive tests are urgently needed incorporating biomarkers to identify patients who will reclassify. MATERIALS AND METHODS: We assessed post-digital rectal examination urine samples of patients on active surveillance for select DNA methylation biomarkers that were previously investigated in radical prostatectomy specimens and shown to correlate with an increasing risk of prostate cancer. Post-digital rectal examination urine samples were prospectively collected from 153 men on active surveillance who were diagnosed with Gleason score 6 disease. Urinary sediment DNA was analyzed for 8 DNA methylation biomarkers by multiplex MethyLight assay. Correlative analyses were performed on gene methylation and clinicopathological variables to test the ability to predict patient risk reclassification. RESULTS: Using backward logistic regression a 4-gene methylation classifier panel (APC, CRIP3, GSTP1 and HOXD8) was identified. The classifier panel was able to predict patient reclassification (OR 2.559, 95% CI 1.257-5.212). We observed this panel to be an independent and superior predictor compared to current clinical predictors such as prostate specific antigen at diagnosis or the percent of tumor positive cores in the initial biopsy. CONCLUSION: We report that a urine based classifier panel of 4 methylation biomarkers predicts disease progression in patients on active surveillance. Once validated in independent active surveillance cohorts, these promising biomarkers may help establish a less invasive method to monitor patients on active surveillance programs.
PURPOSE:Patients with prostate cancer on active surveillance are monitored by repeat prostate specific antigen measurements, digital rectal examinations and prostate biopsies. A subset of patients on active surveillance will later reclassify with disease progression, prompting definitive treatment. To minimize the risk of under treating such patients on active surveillance minimally invasive tests are urgently needed incorporating biomarkers to identify patients who will reclassify. MATERIALS AND METHODS: We assessed post-digital rectal examination urine samples of patients on active surveillance for select DNA methylation biomarkers that were previously investigated in radical prostatectomy specimens and shown to correlate with an increasing risk of prostate cancer. Post-digital rectal examination urine samples were prospectively collected from 153 men on active surveillance who were diagnosed with Gleason score 6 disease. Urinary sediment DNA was analyzed for 8 DNA methylation biomarkers by multiplex MethyLight assay. Correlative analyses were performed on gene methylation and clinicopathological variables to test the ability to predict patient risk reclassification. RESULTS: Using backward logistic regression a 4-gene methylation classifier panel (APC, CRIP3, GSTP1 and HOXD8) was identified. The classifier panel was able to predict patient reclassification (OR 2.559, 95% CI 1.257-5.212). We observed this panel to be an independent and superior predictor compared to current clinical predictors such as prostate specific antigen at diagnosis or the percent of tumor positive cores in the initial biopsy. CONCLUSION: We report that a urine based classifier panel of 4 methylation biomarkers predicts disease progression in patients on active surveillance. Once validated in independent active surveillance cohorts, these promising biomarkers may help establish a less invasive method to monitor patients on active surveillance programs.
Authors: William E Jarrard; Adam Schultz; Tyler Etheridge; Shivashankar Damodaran; Glenn O Allen; David Jarrard; Bing Yang Journal: PLoS One Date: 2019-06-24 Impact factor: 3.240
Authors: Fang Zhao; Ekaterina Olkhov-Mitsel; Shivani Kamdar; Renu Jeyapala; Julia Garcia; Rachel Hurst; Marcelino Yazbek Hanna; Robert Mills; Alexandra V Tuzova; Eve O'Reilly; Sarah Kelly; Colin Cooper; Daniel Brewer; Antoinette S Perry; Jeremy Clark; Neil Fleshner; Bharati Bapat Journal: Clin Epigenetics Date: 2018-11-23 Impact factor: 6.551
Authors: Shivani Kamdar; Ruth Isserlin; Theodorus Van der Kwast; Alexandre R Zlotta; Gary D Bader; Neil E Fleshner; Bharati Bapat Journal: Clin Epigenetics Date: 2019-03-27 Impact factor: 6.551
Authors: Ana Carolina Kerekes Miguez; Bruna D de Figueiredo Barros; Jorge E S de Souza; Cecília Maria L da Costa; Isabela Werneck Cunha; Paula Nicole Vieira P Barbosa; Maria Lúcia P Apezzato; Sandro J de Souza; Dirce Maria Carraro Journal: Cancer Med Date: 2020-06-26 Impact factor: 4.452