AUA 2018: Analysis of Methylated DNA Markers for Prediction of Cancer Progression after Radical Prostatectomy

San Francisco, CA ( Therapeutic decisions for prostate cancer (CAP) are often guided by Gleason grade, which is subjective and lacks precision. In discovery and early validation, the authors identified methylated DNA markers (MDMs) with prognostic association (AUA 2017). In this study, the authors assessed the value of novel MDMs in predicting recurrence using archival tissue from an independent group with > 12 years follow-up after radical prostatectomy (RP).

From 737 men undergoing RP in 2004 at our institution, 446 were randomly selected and 155 met quality criteria. An expert pathologist re-reviewed all specimens in a blinded fashion using updated Gleason criteria and marked tumors for macrodissection prior to DNA extraction, bisulfite treatment and methylation-specific PCR. MDMs were standardized to beta-actin. Recurrence was defined as PSA > 0.4 ng/mL. Top MDMs were selected by regression partitioning tree models to assign recurrence risk and grouped by quartiles (M1 (lowest) to M4 (highest)). Prognostic values of MDMs and Gleason grade groups (GGG) were assessed and compared based on their concordance with postoperative RP outcomes.

Among 155 men studied, 43 recurrences occurred. MDMs selected by the model included WNT3A, AGPS7497, FNBP1, GSDMD, KCNK4, Chr1.61519554, GALR3, and RASSF2. Concordance with post-RP outcomes was 0.85 (95% CI 0.76-0.94) by MDM modeling and 0.63 (CI 0.53-0.71) by GGG, p=0.0001. Concordance was 0.86 (CI 0.77 - 0.95) by combined approaches and did not significantly differ from MDM modeling alone. MDM-defined risk groups are compared to GGG for prediction of CAP recurrence (table). M1 & M2 quartiles showed no recurrences (0/72), yet 36 % (26/72) of these were histologically advanced (GGG 2-5). Conversely, the M4 quartile comprised 69% (34/49) recurrences, and 32% (11) of the 34 accurately predicted by M4 were GGG 1. The figure below compares Kaplan Meier curves between different MDM and Gleason scores.

Methylated DNA Markers 1

Methylated DNA Markers 2
MDMs appear to enhance prediction of CAP recurrence. With optimization and further corroboration, MDMs testing has the potential to contribute objectively to CAP management decisions before & after treatment.

Presented by: Matthew Gettman, MD, Mayo Clinic, Rochester, MN, USA
Co-Authors: Ilya Sobol, Brian Dukek, William Taylor, Douglas Mahoney, Tracy Yab, Calise Berger, John Cheville, Jeffrey Karnes, David Ahlquist, Rochester, MN

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA

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