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

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

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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
Issue number2
StatePublished - Feb 2008


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

ASJC Scopus subject areas

  • Urology


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