Hypermethylation of E-cadherin, p16, p14, and RASSF1A genes in pathologically normal urothelium predict bladder recurrence of bladder cancer after transurethral resection

Lin, Hui-Hui; Ke, Hung-Lung; Wu, Wen-Jeng; Lee, Ying-Huei; Chang, Lin-Li

doi:10.1016/j.urolonc.2010.01.002

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Hypermethylation of E-cadherin, p16, p14, and RASSF1A genes in pathologically normal urothelium predict bladder recurrence of bladder cancer after transurethral resection

Hui-Hui Lin, B.S.
- Department of Microbiology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Hung-Lung Ke, M.D., M.S.
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Wen-Jeng Wu, M.D., Ph.D.
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Ying-Huei Lee, M.D., Ph.D.
- Department of Urology, Chi Mei Medical Center, Tainan, Taiwan
- These authors contributed equally to this work.
Lin-Li Chang, Ph.D.
- Department of Microbiology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Corresponding author. Tel.: +886-7-3121101, ext: 2150; fax: +886-7-3211033.
- These authors contributed equally to this work.

Received 8 October 2009; received in revised form 8 January 2010; accepted 9 January 2010. published online 27 August 2010.
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Abstract

Objectives

This study investigated the hypermethylation of E-cadherin, p16, p14, and RASSF1A in pathologically normal urothelium to predict recurrence of bladder cancer after transurethral resection.

Materials and methods

Samples of bladder tumor and paired pathologically normal urothelium were obtained from 50 bladder cancer patients. The status of promoter hypermethylation in these four genes was investigated by methylation-specific polymerase chain reaction. The clinicopathologic data in these patients were also analyzed in order to evaluate the clinical implication of aberrant methylation in bladder cancer recurrence.

Results

Hypermethylation of E-cadherin (30%), p16 (16%), p14 (14%), and RASSF1A (36%) was detected in the pathologically normal urothelium samples. Promoter hypermethylation occurred frequently in both pathologically normal urothelium and tumor samples from bladder cancer patients, and increased with progression from normal to bladder cancer at E-cadherin (P = 0.067), p16 (P < 0.001), p14 (P = 0.01), and RASSF1A (P = 0.01). No significant correlation was observed between hypermethylation in any genes and muscle/organ invasion and stage/grade, except p14. However, p14 hypermethylation in pathologically normal urothelium samples was associated with shorter recurrence-free interval (P = 0.019).

Conclusions

p14 hypermethylation could be involved in early stage of bladder carcinogenesis, and p14 hypermethylation in pathologically normal urothelium samples should be considered a predictor of bladder cancer recurrence.

Keywords: Gene methylation, Tumor suppressor gene, Bladder cancer, Tumor recurrence

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☆This study was sponsored by the Department of Urology, Chi Mei Medical Center, Tainan, Taiwan, and the Department of Urology, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan (95CM-KMU-08).