A panel of DNA methylation markers reveals extensive methylation in histologically benign prostate biopsy cores from cancer patients

Abstract

BackgroundMen with a negative first prostate biopsy will undergo one or more additional biopsies if they remain at high suspicion of prostate cancer. To date, there are no diagnostic tests capable of identifying patients at risk for a positive diagnosis with the predictive power needed to eliminate unnecessary repeat biopsies. Efforts to develop clinical tests using the epigenetic signature of cores recovered from first biopsies have been limited to a few markers and lack the sensitivity and specificity needed for widespread clinical adoption.MethodsWe developed methylation-specific quantitative polymerase chain reaction assays for a panel of 24 markers that are preferentially methylated in prostate cancer. We modified the bisulfite conversion conditions to allow the integration of the methylation information from multiple markers. We determined the methylation status of the 24 markers in 213 prostate biopsy cores from 104 patients, 37 prostate cancer patients and 67 controls. We performed logistic regression on combinations of markers as well as the entire panel of 24 markers to identify the best candidates for a diagnostic test.ResultsThe marker panel differentiated between cancer cores and benign cores from non-cancer patients with 100% sensitivity and 97% specificity. Furthermore, the panel detected significant methylation in benign cores from prostate cancer patients that was not present in controls. Using methylation of 5 out of 24 to define a cancer case, the analysis of a single benign biopsy core identified 62% of prostate cancer patients undergoing repeat biopsies. ROC curve analysis showed that markers commonly methylated in benign cores from cancer patients are the best candidates for a diagnostic test. The results suggest that 5 to 10 markers will be needed to achieve optimal predictive power.ConclusionsThis study shows that epigenetic field effects differ significantly between cancer patients and controls. Their detection in benign biopsy cores can form the basis of diagnostic tests to identify patients in need of repeat biopsies, reducing the cost of continued PCA screening by up to 40%. They could also be used to identify prostate cancer patients with low grade disease who are likely candidates for active surveillance or focal therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40364-014-0025-9) contains supplementary material, which is available to authorized users.

Comprehensive Evaluation of TFF3 Promoter Hypomethylation and Molecular Biomarker Potential for Prostate Cancer Diagnosis and Prognosis

“…Thus, it would be of potential future clinical relevance to investigate the possible existence of PC-associated TFF3 hypomethylation field effects in morphologically non-malignant prostate needle biopsies, which in turn might be used to predict the need for repeat biopsy. The existence of epigenetic cancer field effects in relation to PC has previously been reported for a number of aberrantly hypermethylated genes [ 48 , 49 , 50 , 51 ], but further studies are needed to investigate if this is also the case for TFF3 promoter hypomethylation. Moreover, non/minimally-invasive biomarkers that can accurately predict the need for initial/repeat prostate biopsy are still lacking.…”

Large‐scale evaluation of SLC18A2 in prostate cancer reveals diagnostic and prognostic biomarker potential at three molecular levels

“…Due to field‐effects, cancer‐specific hypermethylation of certain gene promoters (e.g. GSTP1 ) has been shown to be detectable in morphologically benign prostate tissues adjacent to cancer, and to thus potentially indicate the need for repeat biopsy (Brikun et al., 2014; Trock et al., 2012; Troyer et al., 2009). Of note, in a separate study, we have recently observed that SLC18A2 DNA methylation can be detected in a subset of cancer‐negative diagnostic biopsies from patients with prostate cancer (Møller et al., unpublished data, manuscript in preparation).…”

LogLoss-BERAF: An ensemble-based machine learning model for constructing highly accurate diagnostic sets of methylation sites accounting for heterogeneity in prostate cancer

“…Many large-scale studies have reported an association between PC and methylation alterations in the GRASP gene coding for a general receptor for phosphoinositide-1-associated scaffold protein [ 60 ]. Further research concerning histologically benign prostate biopsy cores from cancer patients suggests that this marker is more likely to be methylated in histologically detectable cancer and may represent later events [ 61 ].…”