Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
PLoS One. 2012;7(2):e31020. doi: 10.1371/journal.pone.0031020. Epub 2012 Feb 24.
To evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2) are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk.
In the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK) were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs) for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls) were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone) were measured using the time-resolved fluoroimmunoassay.
SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05-7.65], 1.24 [95% CI = 1.01-1.53], 1.19 [95% CI = 1.01-1.41], and 1.37 [95% CI = 1.15-1.62], respectively; meta OR = 4.59 [95% CI 2.74-7.70], 1.36 [95% CI = 1.09-1.70], 1.20 [95% CI = 1.00-1.44], and 1.32 [95% CI = 1.10-1.57], respectively). Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05).
Our findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk.
评估编码 CagA 相互作用分子（Src、PTPN11、CRK、CRKL、CSK、c-MET 和 GRB2）的基因是否与胃癌风险相关，以及这些基因与植物雌激素的相互作用是否会改变胃癌风险。
在发现阶段，分析了来自韩国多中心癌症队列的 76 例胃癌新发病例和 322 例匹配对照者的 7 个候选基因中的 137 个候选 SNP。在扩展阶段，对 3 个基因（Src、c-MET 和 CRK）中的 5 个显著 SNP 在 386 例病例和 348 例对照中进行了重新评估。通过调整年龄、吸烟、H. pylori 血清阳性和 CagA 株阳性，估计了胃癌风险的比值比（OR）。在总研究人群（462 例病例和 670 例对照）中，使用合并和荟萃分析呈现了汇总 OR。使用时间分辨荧光免疫测定法测量植物雌激素（染料木黄酮、大豆苷元、雌马酚和肠内酯）的血浆浓度。
Src 的 rs6122566、rs6124914、c-MET 的 rs41739 和 CRK 的 rs7208768 在没有异质性的情况下，在汇总和荟萃分析中均显示出对胃癌的遗传作用（汇总 OR=3.96[95%CI2.05-7.65]、1.24[95%CI=1.01-1.53]、1.19[95%CI=1.01-1.41]和 1.37[95%CI=1.15-1.62]；metaOR=4.59[95%CI2.74-7.70]、1.36[95%CI=1.09-1.70]、1.20[95%CI=1.00-1.44]和 1.32[95%CI=1.10-1.57]）。CRK rs7208768 的风险等位基因在低植物雌激素水平时胃癌风险显著增加（p 交互<0.05）。
我们的研究结果表明，Src、c-MET 和 CRK 通过调节 CagA 信号转导，在胃癌发生中起关键作用，而 CRK 基因与植物雌激素的相互作用改变了胃癌风险。
