Prostate cancer (PCa) is the most frequent cancer in men in the western world, accounting for over 25% of the cancer incidence. Due to the availability of various screening techniques, in particular the prostate-specific antigen (PSA) levels, PCa-related death represents only 10% of all male cancer deaths. Treatment options are typically determined by the expected disease prognosis, mainly guided by Gleason scoring (GS) of cancer-positive biopsies. Because current practice of histopathological examination of prostate biopsy tissue provides limited information and for fear of overtreatment and associated risks, PCa patient management can be improved by combining known risk factors with a more accurate and objective epigenetic diagnostic assay.


One hundred and two men underwent a 12-core prostate biopsy under routine clinical practice. All patient data were de-identified and institutional review board approval was obtained. No evidence of PCa was found in 20 patients, 46 men had GS 6 disease, while the remaining patients all had higher-grade disease, i.e. 35 patients with GS 7, of which 8 had a predominant pattern 4 (GS 4+3), and 1 with GS 8. All individual biopsy cores were epigenetically profiled using quantitative methylation-specific PCR determining the DNA-methylation status of three PCa markers, GSTP1, RASSF1 and APC.


Unsupervised hierarchical clustering was performed identifying men whose core biopsies were highly methylated, of whom nearly 75% had higher-grade disease. High-grade PCa was identifiable through a field effect, since the correlation between increased methylation signals and higher GS prevailed even when cores with GS ≥ 7 were not taken into account. Patients were also stratified according to the national comprehensive cancer network (NCCN) risk categories, resulting in 1 high, 38 intermediate, 12 low and 30 very low risk patients. A positive correlation between NCCN risk and the number of methylation positive cores (Spearman rho = 0.55; p = 3.08e-09) was observed. An epigenetic risk score was developed identifying 79% of high or intermediate risk men, but none of the cancer-free, 40% of the very low risk and 50% of the low risk men.


Epigenetic profiling of GSTP1, RASSF1 and APC of individual biopsy cores could be used to evaluate PCa aggressiveness in an objective manner. Through an epigenetic field effect, potential under-grading due to sampling error could be overcome, resulting in more accurate assessment of GS and patient risk.

Van Neste, Leander; Van Criekinge, Wim; Bigley, Joseph; Grizzle, William E.; Adams, George W.; Kearney, Gary P.; Gaston, Sandra M.
JOURNAL OF UROLOGY, 193 (4):E58-E59; S APR 2015