Effect of DNA methylation on identification of aggressive prostate cancer.
OBJECTIVE
Biochemical (prostate-specific antigen) recurrence of prostate cancer after radical prostatectomy remains a major problem. Better biomarkers are needed to identify high-risk patients. DNA methylation of promoter regions leads to gene silencing in many cancers. In this study, we assessed the effect of DNA methylation on the identification of recurrent prostate cancer.


METHODS
We studied the methylation status of 15 pre-specified genes using methylation-specific polymerase chain reaction on tissue samples from 151 patients with localized prostate cancer and at least 5 years of follow-up after prostatectomy.


RESULTS
On multivariate logistic regression analysis, a high Gleason score and involvement of the capsule, lymph nodes, seminal vesicles, or surgical margin were associated with an increased risk of biochemical recurrence. Methylation of CDH13 by itself (odds ratio 5.50, 95% confidence interval [CI] 1.34 to 22.67; P = 0.02) or combined with methylation of ASC (odds ratio 5.64, 95% CI 1.47 to 21.7; P = 0.01) was also associated with an increased risk of biochemical recurrence. The presence of methylation of ASC and/or CDH13 yielded a sensitivity of 72.3% (95% CI 57% to 84.4%) and negative predictive value of 79% (95% CI 66.8% to 88.3%), similar to the weighted risk of recurrence (determined from the lymph node status, seminal vesicle status, surgical margin status, and postoperative Gleason score), a powerful clinicopathologic prognostic score. However, 34% (95% CI 21% to 49%) of the patients with recurrence were identified by the methylation profile of ASC and CDH13 rather than the weighted risk of recurrence.


CONCLUSIONS
The results of our study have shown that methylation of CDH13 alone or combined with methylation of ASC is independently associated with an increased risk of biochemical recurrence after radical prostatectomy even considering the weighted risk of recurrence score. These findings should be validated in an independent, larger cohort of patients with prostate cancer who have undergone radical prostatectomy.
Alumkal
Joshi J
JJ
Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon, USA.
Zhang
Zhe
Z
Humphreys
Elizabeth B
EB
Bennett
Christina
C
Mangold
Leslie A
LA
Carducci
Michael A
MA
Partin
Alan W
AW
Garrett-Mayer
Elizabeth
E
DeMarzo
Angelo M
AM
Herman
James G
JG
D000328:Adult; D000368:Aged; D019175:DNA Methylation; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence; D012306:Risk
D017430:Prostate-Specific Antigen