Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients.

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 (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.

[1]  J. Herman,et al.  Methylation of the E-cadherin gene in bladder neoplasia and in normal urothelial epithelium from elderly individuals. , 2001, The American journal of pathology.

[2]  J. Herman,et al.  Molecular detection of prostate cancer in urine by GSTP1 hypermethylation. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  J. Herman,et al.  A gene hypermethylation profile of human cancer. , 2001, Cancer research.

[4]  E. Mark,et al.  Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer , 2001, Oncogene.

[5]  J. Minna,et al.  Aberrant promoter methylation of multiple genes in non-small cell lung cancers. , 2001, Cancer research.

[6]  J. Minna,et al.  Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. , 2001, Journal of the National Cancer Institute.

[7]  K. Miller,et al.  Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. , 2000, Cancer research.

[8]  J. Herman,et al.  Predicting lung cancer by detecting aberrant promoter methylation in sputum. , 2000, Cancer research.

[9]  W. Schulz,et al.  DNA Methylation and the Mechanisms of CDKN2A Inactivation in Transitional Cell Carcinoma of the Urinary Bladder , 2000, Laboratory Investigation.

[10]  G. Tse,et al.  High frequency of chromosome 3p deletion in histologically normal nasopharyngeal epithelia from southern Chinese. , 2000, Cancer research.

[11]  F. Khuri,et al.  Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer. , 2000, Journal of the National Cancer Institute.

[12]  W. Lau,et al.  Frequent p15 promoter methylation in tumor and peripheral blood from hepatocellular carcinoma patients. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  J. Herman,et al.  Aberrant methylation of the estrogen receptor and E-cadherin 5' CpG islands increases with malignant progression in human breast cancer. , 2000, Cancer research.

[14]  S. Muto,et al.  Genetic and epigenetic alterations in normal bladder epithelium in patients with metachronous bladder cancer. , 2000, Cancer research.

[15]  G. Liang,et al.  PAX6 methylation and ectopic expression in human tumor cells , 2000, International journal of cancer.

[16]  M. Widschwendter,et al.  Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. , 2000, Journal of the National Cancer Institute.

[17]  S. Groshen,et al.  Progressive increases in de novo methylation of CpG islands in bladder cancer. , 2000, Cancer research.

[18]  J. Herman,et al.  Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. , 2000, Cancer research.

[19]  J. Minna,et al.  ACCELERATED DISCOVERY Promoter Methylation and Silencing of the Retinoic Acid Receptor- Gene in Lung Carcinomas , 2000 .

[20]  François G. Meyer,et al.  Deletions of the INK4A gene in superficial bladder tumors. Association with recurrence. , 1999, The American journal of pathology.

[21]  J. Herman,et al.  Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. , 1999, Blood.

[22]  J. Herman,et al.  Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. , 1999, Cancer research.

[23]  Peter A. Jones,et al.  Cancer-epigenetics comes of age , 1999, Nature Genetics.

[24]  J. Herman,et al.  Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. , 1999, Cancer research.

[25]  J. Herman,et al.  Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. , 1998, Cancer research.

[26]  P. Jones,et al.  The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines. , 1998, Cancer research.

[27]  Peter A. Jones,et al.  DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene , 1997, Oncogene.

[28]  S. Hirohashi,et al.  The E‐cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas , 1997, International journal of cancer.

[29]  S. Leung,et al.  Hypermethylation of the p16 gene in nasopharyngeal carcinoma. , 1996, Cancer research.

[30]  J. Cairns,et al.  Allelotype of human bladder cancer. , 1994, Cancer research.

[31]  S. Lerner,et al.  Role of chromosome 9 in human bladder cancer. , 1993, Cancer research.