DNA methylation biomarkers of prostate cancer: confirmation of candidates and evidence urine is the most sensitive body fluid for non-invasive detection.
BACKGROUND
A prostate cancer (PCa) biomarker with improved specificity relative to PSA is a public health priority. Hypermethylated DNA can be detected in body fluids from PCa patients and may be a useful biomarker, although clinical performance varies between studies. We investigated the performance of candidate PCa DNA methylation biomarkers identified through a genome-wide search.


METHODS
Real-time PCR was used to measure four DNA methylation biomarkers: GSTP1 and three previously unreported candidates associated with the genes RASSF2, HIST1H4K, and TFAP2E in sodium bisulfite-modified DNA. Matched plasma and urine collected prospectively from 142 patients referred for prostate biopsy and 50 young asymptomatic males were analyzed.


RESULTS
Analysis of all biomarkers in urine DNA significantly discriminated PCa from biopsy negative patients. The biomarkers discriminated PCa from biopsy negative patients with AUCs ranging from 0.64 for HIST1H4K (95% CI 0.55-0.72, P < 0.00001) to 0.69 for GSTP1 (95% CI 0.60-0.77, P < 0.00001). All biomarkers showed minimal correlation with PSA. Multivariate analysis did not yield a panel that significantly improved performance over that of single biomarkers. All biomarkers showed greater sensitivity for PCa in urine than in plasma DNA.


CONCLUSIONS
Analysis of the biomarkers in urine DNA significantly discriminated PCa from biopsy negative patients. The biomarkers provided information independent of PSA and may warrant inclusion in nomograms for predicting prostate biopsy outcome. The biomarkers' PCa sensitivity was greater for urine than plasma DNA. The biomarker performances in urine DNA should next be validated in formal training and test studies.
Payne
Shannon R
SR
Epigenomics, Inc., Seattle, Washington 98101, USA. shannon.payne@epigenomics.com
Serth
Jurgen
J
Schostak
Martin
M
Kamradt
Jorn
J
Strauss
Arne
A
Thelen
Paul
P
Model
Fabian
F
Day
J Kevin
JK
Liebenberg
Volker
V
Morotti
Andrew
A
Yamamura
Su
S
Lograsso
Joe
J
Sledziewski
Andrew
A
Semjonow
Axel
A
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000652:urine*; D003581:Cytodiagnosis; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D051549:Glutathione S-Transferase pi / Q000652:urine; D006657:Histones / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000652:urine*; D050656:Transcription Factor AP-2 / Q000652:urine; D025521:Tumor Suppressor Proteins / Q000652:urine; D016482:Urinalysis / Q000379:methods*; D055815:Young Adult
D014408:Biomarkers, Tumor; D006657:Histones; C425300:RASSF2 protein, human; C493680:TFAP2E protein, human; D050656:Transcription Factor AP-2; D025521:Tumor Suppressor Proteins; D004247:DNA; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D017430:Prostate-Specific Antigen