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Prostate. 2015 Nov;75(15):1790-801. doi: 10.1002/pros.23052. Epub 2015 Sep 1.

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

Author information

1
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
2
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada.
3
Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
4
Systems Biology Research Centre, School of Life Sciences, University of Skövde, Skövde, Sweden.
5
Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.
6
Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas.
7
Manitoba Prostate Center, University of Manitoba, Winnipeg, Manitoba, Canada.
8
Department of Epidemiology & Biostatistics, University of Texas Health Science Center, San Antonio, Texas.
9
Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.
10
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas.
11
Department of Urology, University of Texas Health Science Center, San Antonio, Texas.

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. .

KEYWORDS:

DNA methylation; biochemical recurrence; plasma; prostate cancer

PMID:
26332453
DOI:
10.1002/pros.23052
[Indexed for MEDLINE]

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