A133S 多态性和 Ras 相关结构域家族 1A 基因（RASSF1A）启动子超甲基化与中国北方高发地区人群食管和贲门癌的风险相关。
Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern China.
机构信息
Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
出版信息
BMC Cancer. 2013 May 25;13:259. doi: 10.1186/1471-2407-13-259.
BACKGROUND
The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. In this study, the polymorphism, promoter methylation and gene expression of RASSF1A were characterized in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA).
METHODS
We firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay. Then, the promoter methylation status of the RASSF1A in ESCC (n=143), GCA (n=92) and corresponding adjacent normal tissues were further investigated using methylation-specific PCR (MSP) approach. Finally, the RASSF1A protein expression were determined in ESCC (n=27), GCA (n=24) and the matched adjacent normal tissues by immunohistochemical method.
RESULTS
The frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02). Compared with Ala/Ala genotype, Ala/Se and Ser/Ser genotype significantly increased susceptibility to GCA (OR=2.06, 95% CI=1.09-3.97). However, this polymorphism had no association with ESCC (P=0.69). The promoter methylation of RASSF1A gene was significantly increased the risk to both ESCC (OR=5.90, 95% CI=2.78-12.52) and GCA (OR=7.50, 95% CI= 2.78-20.23). Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10-8.73; for differentiation: OR=0.29, 95% CI=0.12-0.69). RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03-0.83). In contrast, there was no statistical significance between RASSF1A positive expression and ESCC. The expression of RASSF1A protein trend to be positively related with older GCA patients (OR=16.20, 95% CI=1.57-167.74).
CONCLUSIONS
The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression. Whereas, RASSF1A hypermethylation may probably also be involved in esophageal squamous cell carcinogenesis.
背景
抑癌基因 RASSF1A 在食管和贲门腺癌的发生发展中的作用尚不清楚。本研究旨在探讨 RASSF1A 的多态性、启动子甲基化和基因表达在食管鳞癌（ESCC）和贲门腺癌（GCA）中的作用。
方法
我们首先采用聚合酶链反应（PCR）和限制性内切酶分析（REA）分析了 228 例 ESCC 患者（n=112）和 GCA 患者（n=116）及 235 例正常对照者中 RASSF1A A133S 的发生率。然后，采用甲基化特异性 PCR（MSP）方法进一步检测了 143 例 ESCC 患者、92 例 GCA 患者及相应的癌旁正常组织中 RASSF1A 的启动子甲基化状态。最后，采用免疫组化法检测了 27 例 ESCC 患者、24 例 GCA 患者及其相应的癌旁正常组织中 RASSF1A 蛋白的表达。
结果
GCA 患者中 133Ala/Ser 和 Ser/Ser 基因型的频率明显高于正常对照组（19.0%比 10.2%，P=0.02）。与 Ala/Ala 基因型相比，Ala/Ser 和 Ser/Ser 基因型显著增加了 GCA 的易感性（OR=2.06，95%CI=1.09-3.97）。然而，这种多态性与 ESCC 无关（P=0.69）。RASSF1A 基因启动子的甲基化显著增加了 ESCC（OR=5.90，95%CI=2.78-12.52）和 GCA（OR=7.50，95%CI=2.78-20.23）的发病风险。ESCC 中 RASSF1A 基因启动子的甲基化也与年龄和癌细胞分化有关（年龄：OR=3.11，95%CI=1.10-8.73；分化：OR=0.29，95%CI=0.12-0.69）。RASSF1A 阳性表达显著降低了 GCA 的发病风险（OR=0.16，95%CI=0.03-0.83）。相反，RASSF1A 阳性表达与 ESCC 之间无统计学意义。RASSF1A 蛋白的表达趋势与年龄较大的 GCA 患者呈正相关（OR=16.20，95%CI=1.57-167.74）。
结论
本研究结果提示，RASSF1A 的改变可能在多态性、启动子高甲基化和蛋白表达水平上在贲门腺癌的发生发展中起重要作用。然而，RASSF1A 高甲基化可能也参与了食管鳞癌的发生。
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