胃癌组织中硫酸酯酶2和WRN基因启动子甲基化与伊立替康药物敏感性的关系

Correlation between the methylation of SULF2 and WRN promoter and chemosensitivity to irinotecan in gastric cancer

目的探讨胃癌组织中硫酸酯酶2（SULF2）和WRN基因启动子甲基化对伊立替康药物敏感性以及胃癌患者临床病理特征的关系。方法采用药物敏感性实验检测伊立替康对102例胃癌新鲜组织的抑制率。采用甲基化特异性聚合酶链反应检测SULF2和WRN基因启动子的甲基化状况，并分析SULF2和WRN基因的甲基化与胃癌患者临床病理特征以及伊立替康敏感性的关系。建立裸鼠移植瘤模型，检测胃癌组织中SULF2基因的甲基化对伊立替康敏感性的影响。结果102例胃癌组织中，SULF2和WRN基因的甲基化率分别为28．4％（29／102）和23．5％（24／102）。SULF2和WRN基因的甲基化与胃癌患者的年龄、性别、病理类型、分化程度、淋巴结转移以及TNM分期均无关（均P〉0．05）。102例胃癌组织中，伊立替康敏感组30例，耐药组72例。敏感组和耐药组胃癌组织中SULF2基因的甲基化率分别为46．7％（14／30）和20．8％（15／72），差异有统计学意义（P=0．008）；WRN基因的甲基化率分别为33．3％（10．／30）和19．4％（14／72），差异无统计学意义（P=0．214）。SULF2和WRN基因均甲基化的胃癌组织对伊立替康的敏感性更高。SULF2基因甲基化胃癌组织的裸鼠移植瘤对于伊立替康的敏感性更高，平均抑瘤率为75．3％。结论SULF2和WRN基因启动子区甲基化检测可能可以为筛选出适宜伊立替康化疗的胃癌患者提供依据。

Objective To explore the relationship between SULF2 and WRN promoter methylation and chemosensitivity to irinotecan, and also the clinicopathological features in patients with gastric cancer. Methods The chemosensitivity to irinotecan was tested by MT＇F assay. The methylation of SULF2 and WRN promoter in the fresh gastric cancer tissues was detected by methylation specific PCR. The differences of chemosensitivity and clinicopathological features of the methylation group were compared with that of the non-methylation group. The tumor growth in nude mice bearing human gastric cancer xenografts treated with CFF-11was also observed. Results The methylation rates of SULF2 and WRN were 28.4% （29/102） and 23.5% （24/102）, respectively. There were no significant association between promoter methylation and clinicopathological features of patients including age, gender, histologic type, lymphatic invasion, and TNM Stage. In all the 102 cases, there were 30 cases of irrinotecan-sensitive group, and 72 cases of the irrinotecan-resistant group. The SULF2 methylation rate was 46.7% （14/30）in the sensitive group, and 20.8% （15/72） in the resistant group （P =0.008） ,The WRN methylation rate was 33.3% （10/30） in the sensitive group, and 19.4% （14/72） in the resistant group （P =0.214）. Gastric cancer tissues were more sensitive to irrinotecan when both the genes were methylated. The nude mice bearing human gastric cancer xenografts with SULF＇2 methylation were more sensitive to irrinotecan. Conclusions The detection of SULF2 and WRN promoter methylation may provide evidence for screening and targeting the most sensitive gastric cancer subpopulation suitable for personalized irrinotecan chemotherapy.