DNA methylation screening of primary prostate tumors identifies SRD5A2 and CYP11A1 as candidate markers for assessing risk of biochemical recurrence

• Published in: The Prostate Vol. 75; no. 15; pp. 1790 - 1801
• Main Authors: Horning, Aaron M., Awe, Julius A., Wang, Chiou-Miin, Liu, Joseph, Lai, Zhao, Wang, Vickie Yao, Jadhav, Rohit R., Louie, Anna D., Lin, Chun-Lin, Kroczak, Tad, Chen, Yidong, Jin, Victor X., Abboud-Werner, Sherry L., Leach, Robin J., Hernandez, Javior, Thompson, Ian M., Saranchuk, Jeff, Drachenberg, Darrel, Chen, Chun-Liang, Mai, Sabine, Huang, Tim Hui-Ming
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-11-2015; Wiley Subscription Services, Inc
• Subjects: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - genetics; Aged; ANTIGEN; ATES OF AMERICA; biochemical recurrence; Biomarkers, Tumor - genetics; CANCER PROGRESSION; Cholesterol Side-Chain Cleavage Enzyme - genetics; CIRCULATING; CpG Islands; Disease-Free Survival; DNA; DNA Methylation; Endocrinology & Metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; FINASTERIDE; GENE-EXPRESSION; GROWTH; Humans; Male; Membrane Proteins - genetics; Middle Aged; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; P13728; plasma; Promoter Regions, Genetic; Prostate - pathology; Prostate - surgery; prostate cancer; Prostatectomy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - surgery; RADICAL PROSTATECTOMY; Risk Factors; SERUM; TESTOSTERONE; Urologi och njurmedicin; Urology & Nephrology; Urology and Nephrology; V108; DNA methylation; prostate cancer; plasma; biochemical recurrence
• ISSN: 0270-4137; 1097-0045; 1097-0045
• DOI: 10.1002/pros.23052

BACKGROUND
Altered DNA methylation in CpG islands of gene promoters has been implicated in prostate cancer (PCa) progression and can be used to predict disease outcome. In this study, we determine whether methylation changes of androgen biosynthesis pathway (ABP)‐related genes in patients' plasma cell‐free DNA (cfDNA) can serve as prognostic markers for biochemical recurrence (BCR).
METHODS
Methyl‐binding domain capture sequencing (MBDCap‐seq) was used to identify differentially methylated regions (DMRs) in primary tumors of patients who subsequently developed BCR or not, respectively. Methylation pyrosequencing of candidate loci was validated in cfDNA samples of 86 PCa patients taken at and/or post‐radical prostatectomy (RP) using univariate and multivariate prediction analyses.
RESULTS
Putative DMRs in 13 of 30 ABP‐related genes were found between tumors of BCR (n = 12) versus no evidence of disease (NED) (n = 15). In silico analysis of The Cancer Genome Atlas data confirmed increased DNA methylation of two loci—SRD5A2 and CYP11A1, which also correlated with their decreased expression, in tumors with subsequent BCR development. Their aberrant cfDNA methylation was also associated with detectable levels of PSA taken after patients' post‐RP. Multivariate analysis of the change in cfDNA methylation at all of CpG sites measured along with patient's treatment history predicted if a patient will develop BCR with 77.5% overall accuracy.
CONCLUSIONS
Overall, increased DNA methylation of SRD5A2 and CYP11A1 related to androgen biosynthesis functions may play a role in BCR after patients' RP. The correlation between aberrant cfDNA methylation and detectable PSA in post‐RP further suggests their utility as predictive markers for PCa recurrence. Prostate 75:1790–1801, 2015. © 2015 Wiley Periodicals, Inc.