CpG island hypermethylation in cell-free serum DNA identifies patients with localized prostate cancer.
BACKGROUND
One of the earliest and most common epigenetic events in prostate carcinogenesis is DNA CpG island (CGI) hypermethylation. Our aim was to analyze the diagnostic and prognostic possibilities of multigene methylation analysis in cell-free serum DNA of prostate cancer (PCA) patients.


METHODS
We analyzed serum samples from 226 consecutive patients (168 PCA; 42 benign prostatic hyperplasia (BPH); 5 incidental PCA; 11 healthy individuals). Cell-free DNA was digested with methylation-sensitive restriction endonucleases (HpaII and HinP1I). Subsequently, CGI hypermethylation at GSTP1, PTGS2, Reprimo, and TIG1 was assessed using real-time PCR.


RESULTS
CGI hypermethylation at GSTP1, TIG1, PTGS2, and Reprimo was more frequent in PCA (42.3%, 9.5%, 2.4%, and 1.2%, respectively) compared to BPH (7.7%, 0%, 0%, and 0%, respectively) and healthy individuals (all 0%) with a statistical significant difference of GSTP1 (P < 0.0001) and TIG1 (P = 0.038). GSTP1 hypermethylation was also detected in four patients with incidental PCA. Hypermethylation in serum DNA at GSTP1 and hypermethylation at any gene site distinguished between PCA and BPH patients in a highly specific (92%) but less sensitive (42-47%) manner. Neither CGI hypermethylation at a single gene loci nor the combination of multiple gene sites was correlated to the pathological stage, grade or biochemical recurrence following radical prostatectomy.


CONCLUSIONS
The detection of aberrant hypermethylation in cell-free serum DNA allows the highly specific diagnosis of PCA. A test based on GSTP1 hypermethylation in serum samples of patients with suspected PCA may help to identify men with increased risk of harboring PCA despite negative prostate biopsy.
Ellinger
Jörg
J
Klinik und Poliklinik für Urologie,Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany. joerg.ellinger@ukb.uni-bonn.de
Haan
Kim
K
Heukamp
Lukas C
LC
Kahl
Philip
P
Büttner
Reinhard
R
Müller
Stefan C
SC
von Ruecker
Alexander
A
Bastian
Patrick J
PJ
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D018899:CpG Islands / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood*; D005820:Genetic Testing / Q000379:methods; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D044967:Serum
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D006023:Glycoproteins; D008565:Membrane Proteins; C452562:RARRES1 protein, human; C412566:RPRM protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi