The Journal of Urology
Volume 179, Issue 2 , Pages 743-747, February 2008

Tissue Inhibitor of Metalloproteinases-3 Promoter Methylation is an Independent Prognostic Factor for Bladder Cancer

  • Mohammad Obaidul Hoque

      Affiliations

    • Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Corresponding Author InformationCorrespondence: Department of Otolaryngology and Head and Neck Surgery, The Johns Hopkins University School of Medicine, 1550 Orleans St., CRB II, 5N.03, Baltimore, Maryland 21231 (telephone: 410-502-5153 or 410-502-8778; FAX: 410-614-1411).
    • Financial interest and/or other relationship with GlaxoSmithKline, Elsevier, Teng, Viventia and Pfizer.
    • ,
  • Shahnaz Begum

      Affiliations

    • Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland
    • ,
  • Mariana Brait

      Affiliations

    • Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • Carmen Jeronimo

      Affiliations

    • Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • Marianna Zahurak

      Affiliations

    • Department of Biostatistics/Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • Kimberly Laskie Ostrow

      Affiliations

    • Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • Eli Rosenbaum

      Affiliations

    • Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • Bruce Trock

      Affiliations

    • The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland
    • ,
  • William H. Westra

      Affiliations

    • Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland
    • ,
  • Mark Schoenberg

      Affiliations

    • The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland
    • ,
  • Steven N. Goodman

      Affiliations

    • Department of Biostatistics/Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • David Sidransky

      Affiliations

    • Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Corresponding Author InformationCorrespondence: Department of Otolaryngology and Head and Neck Surgery, The Johns Hopkins University School of Medicine, 1550 Orleans St., CRB II, 5N.03, Baltimore, Maryland 21231 (telephone: 410-502-5153 or 410-502-8778; FAX: 410-614-1411).
    • Financial interest and/or other relationship with Oncomethylome Sciences.

Received 23 December 2005 published online 14 December 2007.

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.

Key Words: bladder, bladder neoplasms, tissue inhibitor of metalloproteinase-3, tumor markers, biological, methylation

Abbreviations and Acronyms: MMP, matrix metalloproteinase, QMSP, quantitative methylation specific polymerase chain reaction, TIMP, tissue inhibitors of metalloproteinase

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 Study received approval from The Johns Hopkins Hospital institutional review board.Supported by National Cancer Institute Grant U01-CA84986, Oncomethylome Sciences, SA, a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (MOH) and a Young Investigator Award from the International Association for the Study of Lung Cancer (MOH).

PII: S0022-5347(07)02490-1

doi:10.1016/j.juro.2007.09.019

The Journal of Urology
Volume 179, Issue 2 , Pages 743-747, February 2008

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