A panel of DNA methylation markers for the detection of prostate cancer from FV and DRE urine DNA

Abstract

BackgroundEarly screening for prostate cancer (PCA) remains controversial because of overdiagnosis and overtreatment of clinically insignificant cancers. Even though a number of diagnostic tests have been developed to improve on PSA testing, there remains a need for a more informative non-invasive test for PCA. The objective of this study is to identify a panel of DNA methylation markers suitable for a non-invasive diagnostic test from urine DNA collected following a digital rectal exam (DRE) and/or from first morning void (FV). A secondary objective is to determine if the cumulative methylation is indicative of biopsy findings.MethodsDRE and FV urine samples were prospectively collected from 94 patients and analyzed using 24 methylation-specific quantitative PCR assays derived from 19 CpG islands. The methylation of individual markers and various combinations of markers was compared to biopsy results. A methylation threshold for cancer classification was determined using a target specificity of 70%. The average methylation and the number of positive markers were also compared to the result of the biopsy, and the area under the receiver operating characteristic curves (AUCs) were calculated.ResultsMethylation of all 19 markers was detected in FV and DRE DNAs. Combining the methylation of two or more markers improved on individual marker results. Using 6of19 methylated markers as the threshold for cancer classification yielded a specificity of 71% (95% CI, 0.57–0.86) from both DRE and FV and a sensitivity of 89% (95% CI, 0.79–0.97) from DRE and 94% (95% CI, 0.84–1.0) from FV. The negative predictive value at the 6of19 threshold was ≥ 90 for both DNA types.ConclusionsPCA-specific methylation was detected in both FV and DRE DNA. There was no significant difference in diagnostic accuracy at the 6of19 threshold between DRE and FV urine DNA. The results support the development of a non-invasive diagnostic test to reduce unnecessary biopsies in men with elevated PSA. The test can also provide patients with personalized recommendations based on their own methylation profile.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0524-x) contains supplementary material, which is available to authorized users.

Aberrant SOCS3 Promoter Methylation as a Noninvasive Diagnostic Biomarker for Locally Advanced Prostate Cancer

“…However, PSA testing does not discriminate between benign and malignant prostate disease, or between indolent and clinically significant PCa. Therefore, robust and reliable markers are needed to screen, diagnose, and monitor PCa neoplasms 14 , 15 . DNA methylation represents a common, consistent event that may occur early in carcinogenesis and thus it is an attractive biomarker for PCa detection 16 .…”

Development of a multivariable risk model integrating urinary cell DNA methylation and cell‐free RNA data for the detection of significant prostate cancer

“…Single‐gene or expression panels of few genes, such as the PCA3, 11 SelectMDx, 12 ExoDx Prostate(IntelliScore) 13 tests have published promising results to date for the noninvasive detection of significant disease (Gleason score [Gs] ≥7). Similarly, several urine methylation panels have been developed; the ProCUrE assay from Zhao et al 14 quantifies the methylation of HOXD4 and GSTP1 for the detection of CAPRA score 3 to 10 disease, while Brikun et al 15 assessed the binary presence or absence of CpG island methylation associated with 18 genes to predict the presence of any prostate cancer on biopsy. However, these biomarker panels have yet to be widely implemented in clinical settings, and none are currently recommended within the NICE guidelines, 4 suggesting that improvements are required.…”

Epigenetic Biomarkers in Cell-Free DNA and Applications in Liquid Biopsy

“…Such heterogeneity could significantly affect the performance of assays targeting the tissue/tumor-specific DNA methylation biomarkers. To this end, most of the recent cancer testing studies have incorporated a panel of multiple DNA methylation biomarkers and demonstrated diagnostic benefits (Table 1) [104,105]. On the other hand, cfDNA fragmentation pattern analysis is still in its infancy stage and current attempts could only be considered as proof-of-concept studies, considering the limited sample sizes and moderate accuracies [70,74,90,92].…”