胃癌3号染色体短臂抑癌基因 CpG 岛甲基化表型研究

摘要

背景：3号染色体短臂（3p）抑癌基因 CpG 岛甲基化表型（CIMP）涉及的甲基化异常见于多种类型的癌症中，但与胃癌的关系迄今仍未阐明。目的：研究胃癌中3p 抑癌基因启动子区 CIMP 的临床意义。方法：采用甲基化特异性 PCR（MSP）法检测100例胃癌组织及其对应癌旁组织中 hOGG1、VHL、RAR-B、hMLH1、SEMA3B、RASSF1A、BLU和 FHIT 共8个抑癌基因启动子区 CpG 岛甲基化状态。以每份样本中含有4个及以上甲基化基因定义为高 CIMP水平（CIMP-H）。分析 CIMP-H 与胃癌临床病理特征的关系。结果：胃癌组织中 VHL（P =0.030）、hMLH1（P <0.001）、SEMA3B（P =0.003）、RASSF1A（P <0.001）和 FHIT（P <0.001）基因甲基化阳性率显著高于癌旁组织。胃癌组织和对应癌旁组织中 CIMP-H 发生率分别为44.0%和4.0%，差异有统计学意义（ P <0.001）。胃癌组织CIMP-H 与肿瘤分化程度呈显著负相关（P =0.004），与淋巴结转移呈显著正相关（P =0.005），而与性别、年龄、肿瘤部位、肿瘤直径、浸润深度和 TNM 分期均无关（P >0.05）。结论：3p CIMP 异常状态可能在胃癌形成早期已发生，并影响肿瘤分化，导致淋巴结转移。%Background:CpG island methylator phenotype(CIMP)involving tumor suppressor gene( TSG)on short arm of chromosome 3(chromosome 3p)has been found in various types of cancers. However,its correlation with gastric cancer has not been clarified. Aims:To study the clinical significance of CIMP involving TSG on chromosome 3p in gastric cancer. Methods:Methylation specific PCR(MSP)was used to examine methylation profiles for hOGG1,VHL,RAR-B, hMLH1,SEMA3B,RASSF1A,BLU and FHIT harbored in chromosome 3p in 100 gastric cancer and paired paracancerous tissues. High CIMP( CIMP-H)was referred for those samples having four or more synchronously methylated genes. Relationship between CIMP-H and clinicopathological characteristics in gastric cancer was analyzed. Results:Positive methylation rates of VHL(P = 0. 030),hMLH1(P < 0. 001),SEMA3B(P = 0. 003),RASSF1A(P < 0. 001)and FHIT(P < 0. 001)were significantly higher in gastric cancer tissue than in paracancerous tissue. Incidence of CIMP-H rate in gastric cancer tissue was significantly higher than that in paracancerous tissue(44. 0% vs. 4. 0% ,P < 0. 001). CIMP-H was negatively correlated with degree of tumor differentiation(P = 0. 004),and positively correlated with lymph node metastasis(P = 0. 005),but not correlated with gender,age,tumor location,tumor size,depth of infiltration and TNM staging(P > 0. 05). Conclusions:CIMP on chromosome 3p may occur in early stage of oncogenesis of gastric cancer,and influencing tumor differentiation and lymph node metastasis.