Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer

Mohammad Hoque, Shahnaz Begum, Mariana Brait Rodrigues De Oliveira, Carmen Jeronimo, Marianna Zahurak, Kimberly Ostrow, Eli Rosenbaum, Bruce Trock, William H. Westra, Mark Schoenberg, Steven N. Goodman, David Sidransky

Research output: Contribution to journalArticle

Abstract

Purpose: TIMP-3 (tissue inhibitor of metalloproteinases-3) is 1 of 4 members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases. We analyzed TIMP-3 methylation in 175 urine sediment DNA samples from patients with bladder cancer with well characterized clinicopathological parameters, including patient outcome. Materials and Methods: We examined urine sediment DNA for aberrant methylation of 9 genes, including TIMP-3, by quantitative fluorogenic real-time polymerase chain reaction. Results: Using an optimal cutoff value by TaqMan® quantitation we found that the risk of death was statistically significantly higher in patients with higher TIMP-3 and ARF methylation (HR 1.99, 95% CI 1.12 to 3.27, p = 0.01 and HR 1.66, 95% CI 1.00 to 2.76, p = 0.05, respectively) than in patients without/lower TIMP3 and ARF methylation in urine. A significant correlation was also seen between the risk of death and stage 3 tumor (HR 2.73, 95% CI 1.58 to 4.72, p = 0.003) and metastasis (HR 3.32, 95% CI 1.98 to 5.57, p = 0.0001). Multivariate analysis subsequently revealed that TIMP-3 methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis (p = 0.001 and 0.02, respectively). Conclusions: These results suggest that TIMP-3 promoter methylation could be a clinically applicable marker for bladder cancer progression.

Original languageEnglish (US)
Pages (from-to)743-747
Number of pages5
JournalJournal of Urology
Volume179
Issue number2
DOIs
StatePublished - Feb 2008

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Tissue Inhibitor of Metalloproteinase-3
Urinary Bladder Neoplasms
Methylation
Urine
Neoplasm Metastasis
Aptitude
DNA Methylation
Matrix Metalloproteinases
Real-Time Polymerase Chain Reaction
Multivariate Analysis
Survival
DNA
Genes

Keywords

  • Bladder
  • Bladder neoplasms
  • Methylation
  • Tissue inhibitor of metalloproteinase-3
  • Tumor markers, biological

ASJC Scopus subject areas

  • Urology
  • Medicine(all)

Cite this

Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer. / Hoque, Mohammad; Begum, Shahnaz; Brait Rodrigues De Oliveira, Mariana; Jeronimo, Carmen; Zahurak, Marianna; Ostrow, Kimberly; Rosenbaum, Eli; Trock, Bruce; Westra, William H.; Schoenberg, Mark; Goodman, Steven N.; Sidransky, David.

In: Journal of Urology, Vol. 179, No. 2, 02.2008, p. 743-747.

Research output: Contribution to journalArticle

Hoque, Mohammad ; Begum, Shahnaz ; Brait Rodrigues De Oliveira, Mariana ; Jeronimo, Carmen ; Zahurak, Marianna ; Ostrow, Kimberly ; Rosenbaum, Eli ; Trock, Bruce ; Westra, William H. ; Schoenberg, Mark ; Goodman, Steven N. ; Sidransky, David. / Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer. In: Journal of Urology. 2008 ; Vol. 179, No. 2. pp. 743-747.
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abstract = "Purpose: TIMP-3 (tissue inhibitor of metalloproteinases-3) is 1 of 4 members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases. We analyzed TIMP-3 methylation in 175 urine sediment DNA samples from patients with bladder cancer with well characterized clinicopathological parameters, including patient outcome. Materials and Methods: We examined urine sediment DNA for aberrant methylation of 9 genes, including TIMP-3, by quantitative fluorogenic real-time polymerase chain reaction. Results: Using an optimal cutoff value by TaqMan{\circledR} quantitation we found that the risk of death was statistically significantly higher in patients with higher TIMP-3 and ARF methylation (HR 1.99, 95{\%} CI 1.12 to 3.27, p = 0.01 and HR 1.66, 95{\%} CI 1.00 to 2.76, p = 0.05, respectively) than in patients without/lower TIMP3 and ARF methylation in urine. A significant correlation was also seen between the risk of death and stage 3 tumor (HR 2.73, 95{\%} CI 1.58 to 4.72, p = 0.003) and metastasis (HR 3.32, 95{\%} CI 1.98 to 5.57, p = 0.0001). Multivariate analysis subsequently revealed that TIMP-3 methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis (p = 0.001 and 0.02, respectively). Conclusions: These results suggest that TIMP-3 promoter methylation could be a clinically applicable marker for bladder cancer progression.",
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T1 - Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer

AU - Hoque, Mohammad

AU - Begum, Shahnaz

AU - Brait Rodrigues De Oliveira, Mariana

AU - Jeronimo, Carmen

AU - Zahurak, Marianna

AU - Ostrow, Kimberly

AU - Rosenbaum, Eli

AU - Trock, Bruce

AU - Westra, William H.

AU - Schoenberg, Mark

AU - Goodman, Steven N.

AU - Sidransky, David

PY - 2008/2

Y1 - 2008/2

N2 - Purpose: TIMP-3 (tissue inhibitor of metalloproteinases-3) is 1 of 4 members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases. We analyzed TIMP-3 methylation in 175 urine sediment DNA samples from patients with bladder cancer with well characterized clinicopathological parameters, including patient outcome. Materials and Methods: We examined urine sediment DNA for aberrant methylation of 9 genes, including TIMP-3, by quantitative fluorogenic real-time polymerase chain reaction. Results: Using an optimal cutoff value by TaqMan® quantitation we found that the risk of death was statistically significantly higher in patients with higher TIMP-3 and ARF methylation (HR 1.99, 95% CI 1.12 to 3.27, p = 0.01 and HR 1.66, 95% CI 1.00 to 2.76, p = 0.05, respectively) than in patients without/lower TIMP3 and ARF methylation in urine. A significant correlation was also seen between the risk of death and stage 3 tumor (HR 2.73, 95% CI 1.58 to 4.72, p = 0.003) and metastasis (HR 3.32, 95% CI 1.98 to 5.57, p = 0.0001). Multivariate analysis subsequently revealed that TIMP-3 methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis (p = 0.001 and 0.02, respectively). Conclusions: These results suggest that TIMP-3 promoter methylation could be a clinically applicable marker for bladder cancer progression.

AB - Purpose: TIMP-3 (tissue inhibitor of metalloproteinases-3) is 1 of 4 members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases. We analyzed TIMP-3 methylation in 175 urine sediment DNA samples from patients with bladder cancer with well characterized clinicopathological parameters, including patient outcome. Materials and Methods: We examined urine sediment DNA for aberrant methylation of 9 genes, including TIMP-3, by quantitative fluorogenic real-time polymerase chain reaction. Results: Using an optimal cutoff value by TaqMan® quantitation we found that the risk of death was statistically significantly higher in patients with higher TIMP-3 and ARF methylation (HR 1.99, 95% CI 1.12 to 3.27, p = 0.01 and HR 1.66, 95% CI 1.00 to 2.76, p = 0.05, respectively) than in patients without/lower TIMP3 and ARF methylation in urine. A significant correlation was also seen between the risk of death and stage 3 tumor (HR 2.73, 95% CI 1.58 to 4.72, p = 0.003) and metastasis (HR 3.32, 95% CI 1.98 to 5.57, p = 0.0001). Multivariate analysis subsequently revealed that TIMP-3 methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis (p = 0.001 and 0.02, respectively). Conclusions: These results suggest that TIMP-3 promoter methylation could be a clinically applicable marker for bladder cancer progression.

KW - Bladder

KW - Bladder neoplasms

KW - Methylation

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KW - Tumor markers, biological

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