title: Prognostic relevance of methylation markers in patients with non-muscle invasive bladder carcinoma.
abstract: There is increasing evidence for the role of epigenetic gene silencing in superficial bladder cancer. The aim of the current study was to investigate the prognostic value of epigenetic alterations in patients with non-muscle invasive bladder carcinoma. We checked the methylation status of 20 cancer associated genes (p14ARF, p16 CDKN2A, STAT-1, SOCS-1, DR-3, DR-6, PIG-7, BCL-2, H-TERT, BAX, EDNRB, DAPK, RASSF-1A, FADD, TMS-1, E-Cadherin, ICAM-1, TIMP-3, MLH-1, COX-2) for DNA methylation. We analysed microdissected tumour samples from 105 consecutive patients with primary non-muscle invasive bladder carcinoma. Quantitative methylation analysis of CpG sites in the promoter region of the genes was performed with methylation sensitive quantitative real time PCR ('Methylight'). Univariate analysis for association with tumour recurrence was carried out with the Kaplan-Meier analysis and the log-rank test. Follow-up data were available in 95/105 patients (91.4%). A tumour recurrence was observed in 26 patients (27.3%). We could identify six genes (SOCS-1, STAT-1, BCL-2, DAPK, TIMP-3, E-Cadherin), where methylation was associated with tumour recurrence. In Kaplan-Meier analysis, TIMP-3 showed a significant association with recurrence free survival. Methylation of TIMP-3 predicted prolonged disease free interval. In this study, we report a comprehensive analysis on prognostic relevance of gene methylation in non-muscle invasive bladder cancer. We identified one gene (TIMP-3) where methylation was associated with a more favourable outcome. Our data strongly support the usefulness of gene methylation as a prognostic marker in patients with non-muscle invasive bladder cancer.
authors.affiliation: Department of Urology, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA. friedric@uke.uni-hamburg.de
authors.forename: Martin G
authors.initials: MG
authors.lastname: Friedrich
authors.forename: Shahin
authors.initials: S
authors.lastname: Chandrasoma
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cheng
authors.forename: Marieta I
authors.initials: MI
authors.lastname: Toma
authors.forename: Hartwig
authors.initials: H
authors.lastname: Huland
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.forename: Gangning
authors.initials: G
authors.lastname: Liang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D015331:Cohort Studies; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D052138:Genes, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor