CpG island hypermethylation at multiple gene sites in diagnosis and prognosis of prostate cancer.
OBJECTIVE
CpG island hypermethylation causes gene silencing and could be decisive in prostate carcinogenesis and progression. We investigated its role at multiple gene sites during prostate carcinogenesis.


METHODS
A quantitative, methylation-specific polymerase chain reaction was used to analyze the hypermethylation patterns at nine gene loci (Annexin2, APC, EDNRB, GSTP1, PTGS2, MDR1, RARbeta, Reprimo, and TIG1) in 80 patients with prostate cancer (PCa) and 26 patients with benign prostatic hyperplasia (BPH).


RESULTS
Hypermethylation was more frequent in PCa than in BPH tissues (EDNRB, 100% versus 88%; TIG1, 96% versus 12%; RARbeta, 95% versus 35%; GSTP1, 93% versus 15%; APC, 80% versus 50%; MDR1, 80% versus 31%; PTGS2, 68% versus 15%; Reprimo, 59% versus 19%; and Annexin2, 4% versus 0%). TIG1 and GSTP1 hypermethylation distinguished between PCa and BPH with a specificity of greater than 85% and sensitivity of greater than 93%. Hypermethylation at a single gene locus did not correlate with any clinicopathologic variables. In contrast, hypermethylation at two genes (eg, APC and TIG1, APC and GSTP1, APC and PTGS2, APC or MDR, GSTP1 or PTGS2) correlated significantly with the pathologic stage and/or Gleason score (P = 0.033 to 0.045). Hypermethylation at APC and Reprimo, as well as DNA hypermethylation at more than five genes, correlated significantly with the rate of prostate-specific antigen recurrence after radical prostatectomy (P = 0.0078 and P = 0.0074, respectively).


CONCLUSIONS
Our results have confirmed that the hypermethylation patterns are helpful in the diagnosis and prognosis of PCa. Increases in CpG island hypermethylation at multiple gene sites occur during PCa progression and indicate early biochemical recurrence after radical prostatectomy.
Ellinger
Jörg
J
Klinik und Poliklinik für Urologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany. joerg.ellinger@ukb.uni-bonn.de
Bastian
Patrick J
PJ
Jurgan
Thomas
T
Biermann
Katharina
K
Kahl
Philip
P
Heukamp
Lukas C
LC
Wernert
Nicolas
N
Müller
Stefan C
SC
von Ruecker
Alexander
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000368:Aged; D017306:Annexin A2 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D018899:CpG Islands / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019175:DNA Methylation; D020868:Gene Silencing / Q000502:physiology; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D011470:Prostatic Hyperplasia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D012669:Seminal Vesicles / Q000378:metabolism; D012680:Sensitivity and Specificity
C472822:ANXA2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017306:Annexin A2; D018797:Cell Cycle Proteins; 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