ABSTRACT
PURPOSE: Promoter methylation provides an alternative pathway for the loss of tumor suppressor gene functions. This epigenetic change is a new marker for human cancers. We herein investigated the aberrant methylation profile of bladder cancer to identify the epigenetic markers that are useful for the diagnosis of bladder cancer. MATERIALS AND METHODS: Gene promoter methylation was analyzed in 50 bladder transitional cell cancer (TCC) tissues and 30 nonmalignant bladder mucosal tissues including 21 tissue samples with normal histology and 9 tissue samples with inflammation. The methylation status of 13 tumor suppressor genes was analyzed by methylation specific polymerase chain reaction and bisulfite genomic sequencing. The methylation frequency and methylation index were comparatively analyzed in each group of tissues. RESULTS: Bladder TCC showed a high frequency of promoter hypermethylation for RASSF1A(62.0%), RARbeta2(54.0%), E-cadherin(48.0%), p16INK4A(46.0%), p14ARF(34.0%) and H-cadherin(32.0%), whereas, methylation was less common for MGMT(18.0%), DAPK(14.0%) and p15INK4B(10.0%), and methylation was rare for GSTP1(4.0%), FHIT(2.0%), APC(2.0%) and MLH1(2.0%). Benign bladder mucosa rarely showed aberrant methylation except for E-cadherin (10.0%) and RARbeta2(10.0%). The methylation index of bladder TCC(0.25) was significantly higher than that of the benign bladder mucosal tissues(0.03, p<0.01). Remarkably, all of the bladder cancer tissues showed aberrant methylation of at least one of 6 genes including RASSF1A, RARbeta2, p16INK4A, p14ARF, E-cadherin and H-cadherin, whereas only 5 of 30 (16.7%) benign bladder mucosa tissues showed the same findings. CONCLUSIONS: Aberrant promoter methylation of tumor suppressor genes may be a critical step in the development of bladder TCC. Aberrant promoter methylations of RASSF1A, RARbeta2, p16INK4A, p14ARF, E-cadherin and H-cadherin may be promising epigenetic markers for the diagnosis and follow up of bladder cancer.