Zhang Zhi, Yu Dianke, Lu Jie, Zhai Kan, Cao Lei, Rao Juan, Liu Yingwen, Zhang Xuemei, Guo Yongli
Department of Chemotherapy and Radiotherapy, Tangshan Gongren Hospital, Tangshan, China; Institute of Molecular Genetics, College of Life Science, Hebei United University, Tangshan, China.
Department of Etiology of Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PLoS One. 2014 Sep 24;9(9):e108321. doi: 10.1371/journal.pone.0108321. eCollection 2014.
The purpose of this study was to identify functional genetic variants in the promoter of tumor necrosis factor superfamily member 15 (TNFSF15) and evaluate their effects on the risk of developing gastric adenocarcinoma. Forty DNA samples from healthy volunteers were sequenced to identify single nucleotide polymorphisms (SNPs) in the TNFSF15 promoter. Two TNFSF15 SNPs (-358 T > C and -638 A > G) were identified by direct sequencing. Next, genotypes and haplotypes of 470 gastric adenocarcinoma patients and 470 cancer-free controls were analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Serologic tests for Helicobacter pylori infection were measured by enzyme-linked immuno-sorbent assay (ELISA). Subjects carrying the TNFSF15 -358 CC genotype were at an elevated risk for developing gastric adenocarcinoma, compared with those with the -358 TT genotype (OR 1.42, 95% CI, 1.10 to 2.03). H. pylori infection was a risk factor for developing gastric adenocarcinoma (OR 2.31, 95% CI, 1.76 to 3.04). In the H. pylori infected group, subjects with TNFSF15 -358 CC genotype were at higher risks for gastric adenocarcinoma compared with those carrying -358 TT genotype (OR: 2.01, 95%CI: 1.65 to 4.25), indicating that H. pylori infection further influenced gastric adenocarcinoma susceptibility. The -358 T>C polymorphism eliminates a nuclear factor Y (NF-Y) binding site and the -358 C containing haplotypes showed significantly decreased luciferase expression compared with -358 T containing haplotypes. Collectively these findings indicate that functional genetic variants in TNFSF15 may play a role in increasing susceptibility to gastric adenocarcinoma.
本研究的目的是鉴定肿瘤坏死因子超家族成员15（TNFSF15）启动子中的功能性基因变异，并评估它们对胃腺癌发生风险的影响。对40份来自健康志愿者的DNA样本进行测序，以鉴定TNFSF15启动子中的单核苷酸多态性（SNP）。通过直接测序鉴定出两个TNFSF15 SNP（-358 T>C和-638 A>G）。接下来，分析了470例胃腺癌患者和470例无癌对照的基因型和单倍型。通过逻辑回归估计比值比（OR）和95%置信区间（CI）。采用酶联免疫吸附测定（ELISA）检测幽门螺杆菌感染的血清学试验。与携带-358 TT基因型的受试者相比，携带TNFSF15 -358 CC基因型的受试者患胃腺癌的风险升高（OR 1.42，95%CI，1.10至2.03）。幽门螺杆菌感染是胃腺癌发生的一个风险因素（OR 2.31，95%CI，1.76至3.04）。在幽门螺杆菌感染组中，与携带-358 TT基因型的受试者相比，携带TNFSF15 -358 CC基因型的受试者患胃腺癌的风险更高（OR：2.01，95%CI：1.65至4.25），表明幽门螺杆菌感染进一步影响胃腺癌易感性。-358 T>C多态性消除了一个核因子Y（NF-Y）结合位点，与含-358 T的单倍型相比，含-358 C的单倍型显示荧光素酶表达显著降低。这些发现共同表明，TNFSF15中的功能性基因变异可能在增加胃腺癌易感性中起作用。
