A Regulatory Polymorphism at Position-309 in PTPRCAP Is Associated with Susceptibility to Diffuse-type Gastric Cancer and Gene Expression
A Regulatory Polymorphism at Position-309 in PTPRCAP Is Associated with Susceptibility to Diffuse-type Gastric Cancer and Gene Expression
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DOI：
10.1593/neo.91132
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发表时间：
2009-12-01
期刊：
影响因子：
4.8
通讯作者：
Kang, Changwon
中科院分区：
文献类型：
--
作者：
Ju, Hyoungseok;Lim, Byungho;Kang, Changwon
PTPRCAP（CD 45-AP）是蛋白酪氨酸磷酸酶PTPRC（CD 45）的正调节剂，其激活与肿瘤发生有关的Src家族激酶。在本病例对照研究中，PTPRCAP启动子-309位点的单核苷酸多态性（SNP）rs 869736与弥漫型胃癌易感性相关。当将无关的韩国患者与健康对照（n = 406）进行比较时，与主要等位基因纯合子相比，次要等位基因纯合子与弥漫型胃癌（P = 0.0021，n = 252）的易感性增加2.5倍显著相关，但与卵巢型胃癌（P = 0.30，n = 178）无关。其他9个SNP与该SNP几乎完全连锁不平衡（r（2）>= 0.97），显示出相同的关联，并在染色体11q13.1上分布26 kb，覆盖RPS 6 KB 2、PTPRCAP、CORO 1B和GPR 152。然而，在这四个基因中，只有PTPRCAP的表达受到10个SNP单倍型的影响。PTPRCAP的内源性转录水平与来自血液样本的12个淋巴母细胞样细胞中风险单倍型的拷贝数（0，1和2）呈线性相关（P = 0.0060），但其他三个基因的拷贝数则不相关。此外，在荧光素酶报告基因和电泳迁移率变动分析中，rs 869736的癌症风险、次要等位基因T分别比非风险、主要等位基因G增加启动子活性和特异性核蛋白结合亲和力。因此，PTPRCAP启动子中rs 869736的次要等位基因通过增加PTPRCAP表达而与弥漫型胃癌的易感性增加相关，可能导致致癌Src家族激酶的激活。
PTPRCAP (CD45-AP) is a positive regulator of protein tyrosine phosphatase PTPRC (CD45), which activates Src family kinases implicated in tumorigenesis. Single-nucleotide polymorphism (SNP) rs869736 located at position -309 of the PTPRCAP promoter was associated with susceptibility to diffuse-type gastric cancer in the current case-control study. The minor-allele homozygote was significantly associated with a 2.5-fold increased susceptibility to diffuse-type gastric cancer (P = .0021, n = 252), but not to intestinal-type (P = .30, n = 178), versus the major-allele homozygote, when comparing unrelated Korean patients with healthy controls (n = 406). Nine other SNPs were in nearly perfect linkage disequilibrium (r(2) >= 0.97) with this SNP, exhibiting the same association, and spread out for 26 kb on chromosome 11q13.1 covering RPS6KB2, PTPRCAP, CORO1B, and GPR152. Among the four genes, however, only PTPRCAP expression was affected by haplotypes of the 10 SNPs. Endogenous transcript levels of PTPRCAP were linearly correlated with copy numbers (0, 1, and 2) of the risk-haplotype (P = .0060) in 12 lymphoblastoid cells derived from blood samples, but those of the other three genes were not. Furthermore, the cancer-risk, minor-allele T of rs869736 increased both promoter activity and specific nuclear protein-binding affinity than the nonrisk, major-allele G in luciferase reporter and electrophoretic mobility shift assays, respectively. Accordingly, the minor allele of rs869736 in the PTPRCAP promoter is associated with increased susceptibility to diffuse-type gastric cancer by increasing PTPRCAP expression, possibly leading to activation of the oncogenic Src family kinases.