Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy.
OBJECTIVE
To analyze the prognostic significance of six epigenetic biomarkers (APC, Cyclin D2, GSTP1, TIG1, Rassf1A, and RARbeta2 promoter hypermethylation) in a homogeneous group of prostate cancer patients, following radical prostatectomy alone.


METHODS
Biomarker analyses were done retrospectively on tumors from 74 prostate cancer patients all with a Gleason score of 3 + 4 = 7 and minimum follow-up period of 7 years. Using quantitative methylation-specific PCR, we analyzed six gene promoters in primary prostate tumor tissues. Time to any progression was the primary end point, and development of metastatic disease and/or death from prostate cancer was a secondary point. The association of clinicopathologic and biomolecular risk factors to recurrence was done using the log-rank test and Cox proportional hazards model for multivariate analysis. To identify independent prognostic factors, a stepwise selection method was used.


RESULTS
At a median follow-up time of 9 years, 37 patients (50%) had evidence of recurrence: biochemical/prostate-specific antigen relapse, metastases, or death from prostate cancer. In the final multivariate analysis for time to progression (TTP), the significant factors were age > 60 [hazard ratio (HR), 0.4; 95% confidence interval (95% CI), 0.2-0.8; P = 0.01], hypermethylation of GSTP1 (HR, 0.23; 95% CI; 0.09-0.64; P = 0.004), and hypermethylation of APC (HR, 3.0; 95% CI, 1.42-6.32; P = 0.004). In another multivariate analysis, a profile of hypermethylation of APC and cyclin D2 hypermethylation was significant as well: if either any one was hypermethylated (HR, 1.84; 95% CI, 0.92-3.72; P = 0.09) or if both were hypermethylated (HR, 4.3; 95% CI, 1.52-12.33; P = 0.01).


CONCLUSIONS
Methylation status of selected genes in the prostate cancer specimen may predict for time to recurrence in Gleason 3 + 4 = 7 patients undergoing prostatectomy. These results should be validated in a larger and unselected cohort.
Rosenbaum
Eli
E
Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, John Hopkins School of Medicine, Baltimore, MD 21205-2196, USA.
Hoque
Mohammad Obaidul
MO
Cohen
Yoram
Y
Zahurak
Marianna
M
Eisenberger
Mario A
MA
Epstein
Jonathan I
JI
Partin
Alan W
AW
Sidransky
David
D
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D019175:DNA Methylation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008297:Male; D056892:Mediator Complex; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017430:Prostate-Specific Antigen; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; C416944:MED15 protein, human; D056892:Mediator Complex; D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D051549:Glutathione S-Transferase pi; D017430:Prostate-Specific Antigen