探討血漿葉酸、LINE-1基因甲基化與泌尿上皮癌預後之相關性
連啟舜1、許瑮睛2、張議徽1、張菡3、張兆祥1、鍾季容2,4
1中國醫藥大學附設醫院 泌尿部;2中國醫藥大學 健康風險管理學系
The relationship among levels of plasma folate, global DNA hypomethylation, and the disease-free survival of Urothelial carcinoma
Chi-Shun Lien1, Li-Ching Hsu2, Yi-Huei Chang1, Han Chang3, Chao-Hsiang Chang1, Chi-Jung Chung2
1Department of Urology, China Medical University and Hospital, Taichung, Taiwan;2Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan; 3Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
Purpose:
To evaluate the relationship among levels of plasma folate, global DNA methylation and the disease-free survival of urothelial carcinoma (UC).
Materials and Methods:
Total 432 UC cases with no metastasis were recruited at the Department of Urology, China Medical University Hospital in Taiwan. We quantified mean DNA methylation across the 3 CpG sites for LINE-1 using bisulfite-pyrosequencing technology. The plasma folate levels were measured using a competitive immunoassay kit (ADVIA Centaur Folate assay, Siemens) by using the direct chemiluminescent technology. We used a Cox proportional hazard model to calculate the hazard ratio (HR) after adjusting for age at diagnosis, sex, tumor location, tumor stage, grade and other comorbidities.
Results:
During about six year follow-up, total 156 UC cases had adverse effect including recurrence and death. There were 29% of UC patients with plasma folate insufficient (<=6 ng/mL); however we did not found any association between levels of plasma folate and disease-free survival. In blood, DNA hypomethylation of CpG site 1 and site 3 in this LINE-1 region showed shorter disease-free survival (HR=1.70, 95% CI: 1.04-2.77 for site 1 and HR=1.47, 95% CI: 1.01-2.14). After stratified by tumor location, we found similar results for patients with upper urinary tract of cancer (UUTC). For UUTC patients, there were significantly increased 2.84-fold risk of adverse effect observed in patients with tissue levels of DNA methylation <44 compared to those with >=44. In addition, we found the lower levels of DNA methylation in the tissues compared to those in the blood.
Conclusion:
UC patients with DNA hypomethylation were significantly increased the risk of adverse effect after adjustment for potential clinical factors. The mechanisms of DNA hypomethylation involved in the adverse effect may be elucidated in the future.