Abstract
Prostate cancer (PC) diagnosis is based on histological evaluation of prostate needle biopsies, which have high false negative rates. Here, we investigated if cancer-associated epigenetic field effects in histologically normal prostate tissue may be used to increase sensitivity for PC. We focused on nine genes (AOX1, CCDC181 (C1orf114), GABRE, GAS6, HAPLN3, KLF8, MOB3B, SLC18A2, and GSTP1) known to be hypermethylated in PC. Using quantitative methylation-specific PCR, we analysed 66 malignant and 134 non-malignant tissue samples from 107 patients, who underwent ultrasound-guided prostate biopsy (67 patients had at least one cancer-positive biopsy, 40 had exclusively cancer-negative biopsies). Hypermethylation was detectable for all genes in malignant needle biopsy samples (AUC: 0.80 to 0.98), confirming previous findings in prostatectomy specimens. Furthermore, we identified a four-gene methylation signature (AOX1xGSTP1xHAPLN3xSLC18A2) that distinguished histologically non-malignant biopsies from patients with vs. without PC in other biopsies (AUC = 0.65; sensitivity = 30.8%; specificity = 100%). This signature was validated in an independent patient set (59 PC, 36 adjacent non-malignant, and 9 normal prostate tissue samples) analysed on Illumina 450 K methylation arrays (AUC = 0.70; sensitivity = 40.6%; specificity = 100%). Our results suggest that a novel four-gene signature may be used to increase sensitivity for PC diagnosis through detection of epigenetic field effects in histologically non-malignant prostate tissue samples.
Highlights
Prostate cancer (PC) is the second leading cause of cancer in men worldwide[1]
We show that PC-specific hypermethylation of AOX1, CCDC181, GABRE, GAS6, HAPLN3, KLF8, MOB3B, SLC18A2, and GSTP1 can be detected by qMSP even in scarce prostate tissue samples from diagnostic needle biopsies
By analysis of radical prostatectomy (RP) specimens, we have previously identified the eight genes AOX1, CCDC181 (C1orf114), GABRE, GAS6, HAPLN3, KLF8, MOB3B, and SLC18A2 as new common targets of aberrant promoter hypermethylation in PC20–22
Summary
Prostate cancer (PC) is the second leading cause of cancer in men worldwide[1]. In 2012, more than 1.1 million men were diagnosed with PC and an estimated 300,000 men died of the disease[1]. While hypermethylation-based cancer field effects have been demonstrated for GSTP1 in several previous studies of PC24–29, the existence of such epigenetic field effects remains to be investigated for our eight novel candidate methylation marker genes. Results from several previous studies suggest that detection of hypermethylated GSTP1 and APC in cancer-negative prostate biopsies – either only these two genes[26] or in combination with RARB2 (Retinoic Acid Receptor, beta transcript 2)[25] or RASSF128,29 - may hold potential to increase diagnostic sensitivity by predicting a positive repeat biopsy. We show that PC-specific hypermethylation of AOX1, CCDC181, GABRE, GAS6, HAPLN3, KLF8, MOB3B, SLC18A2, and GSTP1 can be detected by qMSP even in scarce prostate tissue samples from diagnostic needle biopsies. To the best of our knowledge, this is the first study to demonstrate significant epigenetic field effects for AOX1, HAPLN3, and SLC18A2 in PC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
