Faculty Collaboration Database

DNA methylation screening of primary prostate tumors identifies SRD5A2 and CYP11A1 as candidate markers for assessing risk of biochemical recurrence. Prostate 2015 Nov;75(15):1790-801

Date

09/04/2015

Pubmed ID

26332453

DOI

10.1002/pros.23052

Scopus ID

2-s2.0-84942830759 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

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. .

Author List

Horning AM, Awe JA, Wang CM, Liu J, Lai Z, Wang VY, Jadhav RR, Louie AD, Lin CL, Kroczak T, Chen Y, Jin VX, Abboud-Werner SL, Leach RJ, Hernandez J, Thompson IM, Saranchuk J, Drachenberg D, Chen CL, Mai S, Huang TH

Author

Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3-Oxo-5-alpha-Steroid 4-Dehydrogenase
Aged
Biomarkers, Tumor
Cholesterol Side-Chain Cleavage Enzyme
CpG Islands
DNA Methylation
Disease-Free Survival
Humans
Male
Membrane Proteins
Middle Aged
Neoplasm Recurrence, Local
Promoter Regions, Genetic
Prostate
Prostatectomy
Prostatic Neoplasms
Risk Factors