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


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(R) 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.
Hoque
Mohammad Obaidul
MO
Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Begum
Shahnaz
S
Brait
Mariana
M
Jeronimo
Carmen
C
Zahurak
Marianna
M
Ostrow
Kimberly Laskie
KL
Rosenbaum
Eli
E
Trock
Bruce
B
Westra
William H
WH
Schoenberg
Mark
M
Goodman
Steven N
SN
Sidransky
David
D
D000368:Aged; D002277:Carcinoma / Q000401:mortality / Q000473:pathology / Q000652:urine*; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic / Q000502:physiology*; D015996:Survival Rate; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000652:urine*; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000473:pathology / Q000652:urine*
D019717:Tissue Inhibitor of Metalloproteinase-3