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Distinct DNA methylation epigenotypes in bladder cancer from different Chinese sub-populations and its implication in cancer detection using voided urine

Pi-Che Chen1, Ming-Hsuan Tsai23, Sidney KH Yip4, Yeong-Chin Jou1, Chi-Fai Ng4, Yanning Chen5, Xiaoling Wang5, Wei Huang6, Chun-Liang Tung7, Gary CW Chen23, Martin MS Huang23, Joanna HM Tong8, Eing-Ju Song9, De-Ching Chang23, Cheng-Da Hsu10, Ka-Fai To8, Cheng-Huang Shen110 and Michael WY Chan23*

Author Affiliations

1 Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan

2 Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan

3 Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan

4 Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China

5 Department of Pathology, Institute of the Forth Hospital of Hebei Medical University, Shijiazhuang, China

6 Department of Medicine, Huaqiao Hospital, Jinan University, Guang zhou, China

7 Department of Pathology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan

8 Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China

9 Department of Bioscience Technology, Chang Jung Christian University, Tainan, Taiwan

10 Department of Medical Research, Chia-Yi Christian Hospital, Chia-Yi, Taiwan

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BMC Medical Genomics 2011, 4:45  doi:10.1186/1755-8794-4-45

Published: 20 May 2011



Bladder cancer is the sixth most common cancer in the world and the incidence is particularly high in southwestern Taiwan. Previous studies have identified several tumor-related genes that are hypermethylated in bladder cancer; however the DNA methylation profile of bladder cancer in Taiwan is not fully understood.


In this study, we compared the DNA methylation profile of multiple tumor suppressor genes (APC, DAPK, E-cadherin, hMLH1, IRF8, p14, p15, RASSF1A, SFRP1 and SOCS-1) in bladder cancer patients from different Chinese sub-populations including Taiwan (104 cases), Hong Kong (82 cases) and China (24 cases) by MSP. Two normal human urothelium were also included as control. To investigate the diagnostic potential of using DNA methylation in non-invasive detection of bladder cancer, degree of methylation of DAPK, IRF8, p14, RASSF1A and SFRP1 was also accessed by quantitative MSP in urine samples from thirty bladder cancer patients and nineteen non-cancer controls.


There were distinct DNA methylation epigenotypes among the different sub-populations. Further, samples from Taiwan and China demonstrated a bimodal distribution suggesting that CpG island methylator phentotype (CIMP) is presented in bladder cancer. Moreover, the number of methylated genes in samples from Taiwan and Hong Kong were significantly correlated with histological grade (P < 0.01) and pathological stage (P < 0.01). Regarding the samples from Taiwan, methylation of SFRP1, IRF8, APC and RASSF1A were significantly associated with increased tumor grade, stage. Methylation of RASSF1A was associated with tumor recurrence. Patients with methylation of APC or RASSF1A were also significantly associated with shorter recurrence-free survival. For methylation detection in voided urine samples of cancer patients, the sensitivity and specificity of using any of the methylated genes (IRF8, p14 or sFRP1) by qMSP was 86.7% and 94.7%.


Our results indicate that there are distinct methylation epigenotypes among different Chinese sub-populations. These profiles demonstrate gradual increases with cancer progression. Finally, detection of gene methylation in voided urine with these distinct DNA methylation markers is more sensitive than urine cytology.