Marsit Carmen J, Karagas Margaret R, Schned Alan, Kelsey Karl T
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Ann N Y Acad Sci. 2006 Sep;1076:810-21. doi: 10.1196/annals.1371.031.
Tobacco smoking, certain occupational exposures, and exposure to inorganic arsenic in drinking water have been associated with the occurrence of bladder cancer. However, in these tumors the exposure-associated pattern of somatic alterations in genes in the causal pathway for disease has been poorly characterized. Animal and in vitro studies have suggested that arsenic, tobacco carcinogens, and other exposures may act through epigenetic mechanisms. We, therefore, examined, in a population-based study of human bladder cancer (n = 351), the relationship between epigenetic silencing of the tumor-suppressor genes, p16(INK4A), RASSF1A, PRSS3, and the four SFRP genes and exposure to both tobacco and arsenic in bladder cancer. Promotor methylation silencing of each of these genes occurred in approximately 30-50% of bladder cancers. Epigenetic silencing of RASSF1A and PRSS3 and any of the SFRP genes were each significantly associated with advanced tumor stage (P < 0.001, P < 0.04, and P < 0.005, respectively). Arsenic exposure, measured as toenail arsenic, was associated with RASSF1A (P < 0.02) and PRSS3 (P < 0.1) but not p16(INK4A) or SFRP promotor methylation, in models adjusted for stage and other risk factors. Cigarette smoking was associated with a greater than twofold increased risk of promotor methylation of the p16(INK4A) gene, with greater risk seen in patients with exposures more recent to disease diagnosis, and smoking was also significantly associated with any SFRP gene methylation (P < 0.01). These results from human bladder tumors, add to the body of animal and in vitro evidence that suggests bladder carcinogens play a crucial role in the induction of important epigenetic alterations.
吸烟、某些职业暴露以及饮用水中无机砷的接触都与膀胱癌的发生有关。然而，在这些肿瘤中，疾病因果途径中基因的体细胞改变的暴露相关模式尚未得到充分描述。动物和体外研究表明，砷、烟草致癌物和其他暴露可能通过表观遗传机制起作用。因此，在一项基于人群的人类膀胱癌研究（n = 351）中，我们研究了肿瘤抑制基因p16(INK4A)、RASSF1A、PRSS3和四个SFRP基因的表观遗传沉默与膀胱癌中烟草和砷暴露之间的关系。这些基因中的每一个的启动子甲基化沉默在大约30 - 50%的膀胱癌中发生。RASSF1A和PRSS3以及任何一个SFRP基因的表观遗传沉默均与肿瘤晚期显著相关（分别为P < 0.001、P < 0.04和P < 0.005）。在根据分期和其他风险因素进行调整的模型中，以趾甲砷测量的砷暴露与RASSF1A（P < 0.02）和PRSS3（P < 0.1）相关，但与p16(INK4A)或SFRP启动子甲基化无关。吸烟与p16(INK4A)基因启动子甲基化风险增加两倍以上相关，在疾病诊断时近期有暴露的患者中风险更高，并且吸烟也与任何SFRP基因甲基化显著相关（P < 0.01）。来自人类膀胱肿瘤的这些结果，补充了动物和体外证据，表明膀胱致癌物在重要表观遗传改变的诱导中起关键作用。
