DNA methylation screening of primary prostate tumors identifies SRD5A2 and CYP11A1 as candidate markers for assessing risk of biochemical recurrence.
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. .
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Aaron M
AM
Horning
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada.|Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Systems Biology Research Centre, School of Life Sciences, University of Skövde, Skövde, Sweden.
Julius A
JA
Awe
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Chiou-Miin
CM
Wang
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Joseph
J
Liu
Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.|Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas.
Zhao
Z
Lai
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Vickie Yao
VY
Wang
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Rohit R
RR
Jadhav
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Anna D
AD
Louie
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Chun-Lin
CL
Lin
Manitoba Prostate Center, University of Manitoba, Winnipeg, Manitoba, Canada.
Tad
T
Kroczak
Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.|Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas.|Department of Epidemiology & Biostatistics, University of Texas Health Science Center, San Antonio, Texas.
Yidong
Y
Chen
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.|Department of Epidemiology & Biostatistics, University of Texas Health Science Center, San Antonio, Texas.
Victor X
VX
Jin
Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.
Sherry L
SL
Abboud-Werner
Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.|Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas.|Department of Urology, University of Texas Health Science Center, San Antonio, Texas.
Robin J
RJ
Leach
Department of Urology, University of Texas Health Science Center, San Antonio, Texas.
Javior
J
Hernandez
Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.|Department of Urology, University of Texas Health Science Center, San Antonio, Texas.
Ian M
IM
Thompson
Manitoba Prostate Center, University of Manitoba, Winnipeg, Manitoba, Canada.
Jeff
J
Saranchuk
Manitoba Prostate Center, University of Manitoba, Winnipeg, Manitoba, Canada.
Darrel
D
Drachenberg
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Chun-Liang
CL
Chen
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada.
Sabine
S
Mai
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.|Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.
Tim Hui-Ming
TH
Huang
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000473:pathology / Q000601:surgery; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D012307:Risk Factors
D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D002786:Cholesterol Side-Chain Cleavage Enzyme; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human
DNA methylation; biochemical recurrence; plasma; prostate cancer