Effect of DNA Methylation on Identification of Aggressive Prostate Cancer

Joshi J. Alumkal, Zhe Zhang, Elizabeth B. Humphreys, Christina Bennett, Leslie A. Mangold, Michael A Carducci, Alan Wayne Partin, Elizabeth Garrett-Mayer, Angelo Michael Demarzo, James G. Herman

Research output: Contribution to journalArticle

Abstract

Objectives: 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.

Original languageEnglish (US)
Pages (from-to)1234-1239
Number of pages6
JournalUrology
Volume72
Issue number6
DOIs
StatePublished - Dec 2008

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DNA Methylation
Methylation
Prostatic Neoplasms
Recurrence
Prostatectomy
Confidence Intervals
Neoplasm Grading
Seminal Vesicles
Lymph Nodes
Odds Ratio
Gene Silencing
Prostate-Specific Antigen
Genetic Promoter Regions
Capsules
Biomarkers
Logistic Models
Regression Analysis
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Urology

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Alumkal, J. J., Zhang, Z., Humphreys, E. B., Bennett, C., Mangold, L. A., Carducci, M. A., ... Herman, J. G. (2008). Effect of DNA Methylation on Identification of Aggressive Prostate Cancer. Urology, 72(6), 1234-1239. https://doi.org/10.1016/j.urology.2007.12.060

Effect of DNA Methylation on Identification of Aggressive Prostate Cancer. / Alumkal, Joshi J.; Zhang, Zhe; Humphreys, Elizabeth B.; Bennett, Christina; Mangold, Leslie A.; Carducci, Michael A; Partin, Alan Wayne; Garrett-Mayer, Elizabeth; Demarzo, Angelo Michael; Herman, James G.

In: Urology, Vol. 72, No. 6, 12.2008, p. 1234-1239.

Research output: Contribution to journalArticle

Alumkal, JJ, Zhang, Z, Humphreys, EB, Bennett, C, Mangold, LA, Carducci, MA, Partin, AW, Garrett-Mayer, E, Demarzo, AM & Herman, JG 2008, 'Effect of DNA Methylation on Identification of Aggressive Prostate Cancer', Urology, vol. 72, no. 6, pp. 1234-1239. https://doi.org/10.1016/j.urology.2007.12.060
Alumkal JJ, Zhang Z, Humphreys EB, Bennett C, Mangold LA, Carducci MA et al. Effect of DNA Methylation on Identification of Aggressive Prostate Cancer. Urology. 2008 Dec;72(6):1234-1239. https://doi.org/10.1016/j.urology.2007.12.060
Alumkal, Joshi J. ; Zhang, Zhe ; Humphreys, Elizabeth B. ; Bennett, Christina ; Mangold, Leslie A. ; Carducci, Michael A ; Partin, Alan Wayne ; Garrett-Mayer, Elizabeth ; Demarzo, Angelo Michael ; Herman, James G. / Effect of DNA Methylation on Identification of Aggressive Prostate Cancer. In: Urology. 2008 ; Vol. 72, No. 6. pp. 1234-1239.
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abstract = "Objectives: 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.",
author = "Alumkal, {Joshi J.} and Zhe Zhang and Humphreys, {Elizabeth B.} and Christina Bennett and Mangold, {Leslie A.} and Carducci, {Michael A} and Partin, {Alan Wayne} and Elizabeth Garrett-Mayer and Demarzo, {Angelo Michael} and Herman, {James G.}",
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T1 - Effect of DNA Methylation on Identification of Aggressive Prostate Cancer

AU - Alumkal, Joshi J.

AU - Zhang, Zhe

AU - Humphreys, Elizabeth B.

AU - Bennett, Christina

AU - Mangold, Leslie A.

AU - Carducci, Michael A

AU - Partin, Alan Wayne

AU - Garrett-Mayer, Elizabeth

AU - Demarzo, Angelo Michael

AU - Herman, James G.

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N2 - Objectives: 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.

AB - Objectives: 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.

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