Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Gastroenterology. 2011 Mar;140(3):892-902. doi: 10.1053/j.gastro.2010.10.058. Epub 2010 Nov 8.
BACKGROUND & AIMS: Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated.
We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants.
A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38).
MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.
两种主要类型的胃癌，肠型和弥漫型，通过不同的机制发展；弥漫型被认为更多地受到遗传因素的影响，尽管其机制尚不清楚。我们之前的全基因组关联研究将 3 个单核苷酸多态性（SNP）与弥漫型胃癌（DGC）相关联；其中 1 个是前列腺干细胞抗原（PSCA）中的功能性 SNP（rs2294008），但另外 2 个的位置尚未研究。
我们进行高密度图谱绘制以探索染色体 1q22 上这 2 个 SNP 的连锁不平衡状态。使用来自 606 例病例和 1264 例对照（均为日本个体）的 DNA 进行 DGC 病例对照研究，并使用来自日本（304 例病例，1465 例对照）和韩国（452 例病例，372 例对照）个体的 DNA 进行验证。通过报告基因检测和剪接变体分析来分析 SNP 对功能的影响。
与这 2 个 SNP 强烈连锁不平衡的区域包含粘蛋白 1（MUC1）和其他 4 个基因，并且与 DGC 显著相关（rs2070803：P=4.33×10(-13)；通过 3 个研究小组的荟萃分析，比值比[OR]为 1.71），但与肠型胃癌无关。功能研究表明，MUC1 中的 rs4072037（P=1.43×10(-11)；通过荟萃分析，OR 为 1.66）影响启动子活性，并决定胃上皮中 MUC1 的主要剪接变体。携带 PSCA 中的 rs2294008 和 MUC1 中的 rs4072037 这 2 个 SNP 的个体发生 DGC 的风险较高（OR，8.38）。
MUC1 是鉴定出的第二个主要的 DGC 易感性基因。MUC1 中的 rs2070803 和 rs4072037 可能用于识别此类胃癌的高危个体。
