本人與計劃共同主持人北醫薛玉梅教授在十二年追蹤研究中證實尿液砷代謝型態與泌 尿上皮癌危險性有顯著相關。且在2010 年發表研究證實血漿中葉酸含量越低且同半胱 胺酸含量越高罹患泌尿上皮癌風險性顯著越高。其它葉酸相關單碳代謝因子，包括： S-adenosylmethionine(SAM)和其代謝物S-adenosylhomocysteine(SAH)，其含量高低不僅 反映飲食葉酸補充量，且因SAM 主要提供細胞和尿液砷代謝甲基化反應甲基之主要來 源，故SAM/SAH 比值也反映細胞DNA 甲基化程度，進而與癌症發生有關。故本研究 計畫為期三年，探討整體性DNA 甲基化程度、單碳代謝因子、尿液砷代謝型態、甘胺 酸氮甲基轉化酵素(Glycine N-methyltransferase; GNMT)基因多形性與泌尿上皮癌的相 關性。第一年研究目的主要測量血漿中葉酸、同半胱胺酸、S-adenosylmethionine 與 S-adenosylhomocysteine，評估其與尿液砷代謝型態對泌尿上皮癌之交互作用。第二年 研究目的為建立組織免疫染色方法，比較患者膀胱組織和週邊血液兩者間整體性DNA 甲基化程度的差異，並評估尿液砷代謝型態、血漿單碳代謝因子和DNA 甲基化程度對 泌尿上皮癌的交互作用關係。最後第三年研究目的為分析甲基化相關酵素GNMT 基因 多形性與單倍體變異情形(haplotype)與整體性DNA 低度甲基化程度對泌尿上皮癌的影 響。預計藉由本計劃可暸解SAM/SAH 比值高低是否藉由改變尿中砷物種型態和整體 性DNA 甲基化而與泌尿上皮癌發生有關。
We previously pointed out the significant association between urinary arsenic profiles and urothelial carcinoma (UC) risk through a 12-year follow-up study. Futher, we observed the increased UC risk in people with lower plasma folate and higher homocysteine than those with higher plasma folate and lower homocysteine in 2010. S-adenosylmethionine (SAM) is one factor included in one-carbon metabolism pathway and is the main donor of methyl group in cells. The ratio of SAM and its metabolite S-adenosylhomocysteine (SAH) not only reflected the intake level of dietary folate but also demonstrated the extent of global DNA methylation. These factors might play important roles in UC carcinogenesis. We would expecte to take three years to explore the interactions among global DNA methylation, one-carbon metabolic pathway factors, urinary arsenic profiles, the polymorphisms and haplotype of Glycine N-methyltransferase (GNMT) and UC. In the first year, we would measure the levels of plasma folate, homocysteine, SAM and SAH and evaluate the associations between these factors and UC risk. In the second year, we would set up the method of immunohistochemistry stain and compare the differences between the global DNA methylation from bladder tissues and blood. In the last year, we would analyze the GNMT gene polymorphism and haplotype variation. At the same time, we would explore the impact of GNMT genetic variation and global DNA methylation on UC risk. Based on the results from our research, we might propose that the decreased ratio of SAM/SAH resulted in UC risk increased. This mechanism might be through the changed levels of urinary arsenic profiles and global DNA methylation.
