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Clinical Cancer Research Vol. 8, 464-470, February 2002
© 2002 American Association for Cancer Research


Molecular Oncology, Markers, Clinical Correlates

Hypermethylation of Multiple Genes in Tumor Tissues and Voided Urine in Urinary Bladder Cancer Patients

Michael W. Y. Chan, Lun W. Chan, Nelson L. S. Tang, Joanna H. M. Tong, Kwok W. Lo, Tin L. Lee, Ho Y. Cheung, Wai S. Wong, Peter S. F. Chan, Fernand M. M. Lai and Ka F. To1

Departments of Anatomical and Cellular Pathology [M. W. Y. C., J. H. M. T., K. W. L., T. L. L., F. M. M. L., K. F. T.], Surgery [L. W. C., H. Y. C., W. S. W., P. S. F. C.], and Chemical Pathology [N. L. S. T.], The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, People’s Republic of China

Purpose: We aimed to investigate the methylation pattern in bladder cancer and assess the diagnostic potential of such epigenetic changes in urine.

Experimental Design: The methylation status of 7 genes (RARß, 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 RARß (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, RARß, 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 RARß (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 RARß 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 RARß, 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.




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Copyright © 2002 by the American Association for Cancer Research.