title: Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients.
abstract: OBJECTIVE
  We aimed to investigate the methylation pattern in bladder cancer and assess the diagnostic potential of such epigenetic changes in urine.
  
  
  METHODS
  The methylation status of 7 genes (RARbeta, DAPK, E-cadherin, p16, p15, GSTP1, and MGMT) in 98 cases of bladder transitional cell carcinoma and 4 cases of carcinoma in situ was analyzed by methylation-specific PCR. Twenty-two cases had paired voided urine samples for analysis.
  
  
  RESULTS
  In transitional cell carcinoma tumor tissues, aberrant methylation was frequently detected in RARbeta (87.8%), DAPK (58.2%), E-cadherin (63.3%), and p16 (26.5%), whereas methylation of p15 (13.3%), GSTP1 (5.1%), and MGMT (5.1%) is not common. No association between methylation status and grading or muscle invasiveness was demonstrated. In 22 paired voided urine samples of bladder cancer, methylation of DAPK, RARbeta, E-cadherin, and p16 could be detected in 45.5%, 68.2%, 59.1%, and 13.6% of the cases, respectively. The sensitivity of methylation analysis (90.9%) was higher than that of urine cytology (45.5%) for cancer detection. Methylation of RARbeta(50%), DAPK (75%), and E-cadherin (50%) was also detected in carcinoma in situ. In 7 normal urothelium samples and 17 normal urine controls, no aberrant methylation was detected except for RARbeta methylation in 3 normal urothelium samples (42.9%) and 4 normal urine samples (23.5%), respectively.
  
  
  CONCLUSIONS
  Our results demonstrated a distinct methylation pattern in bladder cancer with frequent methylation of RARbeta, DAPK, E-cadherin, and p16. Detection of gene methylation in routine voided urine using selected markers appeared to be more sensitive than conventional urine cytology.
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, People's Republic of China.
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
authors.forename: Lun W
authors.initials: LW
authors.lastname: Chan
authors.forename: Nelson L S
authors.initials: NL
authors.lastname: Tang
authors.forename: Joanna H M
authors.initials: JH
authors.lastname: Tong
authors.forename: Kwok W
authors.initials: KW
authors.lastname: Lo
authors.forename: Tin L
authors.initials: TL
authors.lastname: Lee
authors.forename: Ho Y
authors.initials: HY
authors.lastname: Cheung
authors.forename: Wai S
authors.initials: WS
authors.lastname: Wong
authors.forename: Peter S F
authors.initials: PS
authors.lastname: Chan
authors.forename: Fernand M M
authors.initials: FM
authors.lastname: Lai
authors.forename: Ka F
authors.initials: KF
authors.lastname: To
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism / Q000652:urine; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000652:urine; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000378:metabolism / Q000652:urine*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000652:urine*
chemical_list: D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases