Abstract 4705: Distinct gene promoter hypermethylation profile in bladder cancer patients from different Chinese populations and its implication in cancer detection using voided urine samples

Abstract

Abstract Bladder cancer is the 6th most common cancer in the world and the incidence is particularly high in southwestern Taiwan. Bladder cancer patients would need to have long term follow-up and repeated urine cytology, however the sensitivity for urine cytology is known to be low. Several studies including ours had identified several tumor-related genes that are hypermethylated in bladder cancer patients and can be detected in voided urine samples (Chan et al., Clin Cancer Res 8: 464-470, 2002). However, comprehensive methylation profile of bladder cancer in Taiwan is currently unknown. On the other hand, studies also suggested that the non-random methylation profile in cancer may be related to the exposure of different environmental carcinogen in different locality. In this regard, we aim to investigate the DNA methylation profile of multiple tumor suppressor genes in bladder cancer patients from different Chinese populations including Taiwan (104 cases), Hong Kong (98 cases) and Beijing (24 cases) by methylation specific PCR (MSP). Genes showing distinct methylation in Taiwanese population will be selected as biomarkers for cancer detection in voided urine samples. Our result showed that frequent methylation was detected in p14 (84.4%), IRF8 (67.4%), sFRP1 (62.8%), and DAPK (52.2%) from cancer patients of Taiwan. While methylation was also detected in RASSF1A (37.0%), p15 (32.6%), APC (28.3%), hMLH1 (21.7%), SOCS-1 (19.6%), and CDH1 (15.2%). The methylation profile demonstrated bimodal distribution which is a characteristic of CpG island methylator phentotype (CIMP). Besides, the number of methylated genes in each patient were significantly correlated with pathological grade (P <0.001) and stage (P<0.05). Interestingly, methylation of CDH1, hMLH1, p14 and p15 showed obvious diversity among different Chinese populations. Importantly, the sensitivity and specificity of methylation detection of any one of the methylated gene (IRF8, p14, sFRP1 and RASSF1A) in voided urine of patients using qMSP is 89.5% and 94.4% respectively. To further identify novel targets that are epigenetically silenced in bladder cancer from Taiwan, we performed differential methylation analysis (DMH) using Agilent 244K CpG island microarray coupled with expression microarray in BFTC905 and TSGH8301 bladder cancer cell lines. ARHGEF17 and CDKN1C were identified to be concurrently methylated in these two bladder cancer cell lines as compared with SV-HUC-1 normal bladder cell line. In conclusion, our result indicated that there are distinct DNA methylation profiles among different Chinese 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4705.