Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer
Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer
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DOI：
10.1038/ng.152
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发表时间：
2008-06-01
期刊：
影响因子：
30.8
通讯作者：
Hirohashi, Setsuo
中科院分区：
文献类型：
--
作者：
Sakamoto, Hiromi;Yoshimura, Kimio;Hirohashi, Setsuo
胃癌分为肠型和弥漫型，后者包括一种高度恶性的形式，可塑性胃炎。两阶段全基因组关联研究（第1阶段：188例病例和752例参考文献的85，576个SNP;第2阶段：在日本，749例病例和750例对照中的2，753个SNP）确定了内含子SNP（rs 2976392）在PSCA中（前列腺干细胞抗原）和弥漫型胃癌（等位基因特异性比值比（OR）1.62，95% CI = 1.38-1.89，P = 1.11 × 10 - 9）。这种相关性在直肠型胃癌中的意义要小得多。我们发现PSCA在分化的胃上皮细胞中表达，在体外具有细胞增殖抑制活性，并且在胃癌中经常沉默。在第一外显子中的SNP（rs 2294008，其具有r（2）= 0.995，D' = 0.999，具有rs 2976392）处用风险等位基因T取代C等位基因降低基因上游片段的转录活性。在韩国457例患者和390例对照者中，同样的危险等位基因也与弥漫型胃癌显著相关（等位基因特异性OR 1.90，95%CI = 1.56-2.33，P = 8.01 × 10 - 11）。PSCA基因多态性可能参与调节胃上皮细胞增殖，影响弥漫型胃癌的易感性。
Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.