Rokavec Matjaz, Justenhoven Christina, Schroth Werner, Istrate Monica Adina, Haas Susanne, Fischer Hans-Peter, Vollmert Caren, Illig Thomas, Hamann Ute, Ko Yon-Dschun, Glavac Damjan, Brauch Hiltrud
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
Clin Cancer Res. 2007 Dec 15;13(24):7506-14. doi: 10.1158/1078-0432.CCR-07-0457.
The receptor tyrosine kinase ERBB4/HER4 plays a role in cell division, migration, differentiation, as well as apoptosis, and is frequently overexpressed in breast and colorectal tumors. To understand the role of genetic variations in the regulation of ERBB4 expression, we identified new polymorphisms and investigated their functional implication and risk association with breast and colorectal cancer.
We screened colorectal tumors from 92 patients for genetic variants at the ERBB4 ATG -1000 bp 5'-regulatory region by denaturing high-performance liquid chromatography and sequencing. Variants were subjected to DNA-protein interaction analyses (electrophoretic mobility shift assay), reporter gene assays in breast cancer cell lines MDA134 and MDA157, and immunohistochemical analyses of breast tumors. We established genotype frequencies within a breast cancer case-control collection (1,021 cases, 1,015 population-based controls) and a colorectal cancer case-control collection (459 cases, 569 blood donors) using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were assessed by multivariate logistic regression.
We identified five new germ line variants -815 A>T, -782 G>T, -638 insTC, -267 C>G, and -219 del10bp. Two variants showed in vitro functional effects. The -782T allele showed lower protein binding affinity and lower promoter activity compared with the -782G allele, however, the -815T allele showed higher protein binding affinity and higher promoter activity. The -782T variant was identified as a risk allele for breast and colorectal cancer (OR, 1.59; 95% CI, 1.06-2.34 and OR, 2.21; 95% CI, 1.22-3.99, respectively).
The ERBB4 -782 G>T polymorphism, by virtue of its in vitro functional implication and incidence, is a risk factor for breast and colorectal cancer.
受体酪氨酸激酶ERBB4/HER4在细胞分裂、迁移、分化以及细胞凋亡中发挥作用，且在乳腺癌和结直肠癌中经常过度表达。为了解基因变异在ERBB4表达调控中的作用，我们鉴定了新的多态性，并研究了它们的功能意义以及与乳腺癌和结直肠癌的风险关联。
我们通过变性高效液相色谱法和测序，对92例患者的结直肠癌肿瘤在ERBB4 ATG -1000 bp 5'-调控区域进行基因变异筛查。对变异进行DNA-蛋白质相互作用分析（电泳迁移率变动分析）、在乳腺癌细胞系MDA134和MDA157中进行报告基因分析，以及对乳腺肿瘤进行免疫组织化学分析。我们使用基质辅助激光解吸电离/飞行时间质谱法在乳腺癌病例对照队列（1021例病例，1015例基于人群的对照）和结直肠癌病例对照队列（459例病例，569例献血者）中确定基因型频率。通过多变量逻辑回归评估调整后的比值比（OR）和95%置信区间（CI）。
我们鉴定出五个新的种系变异——-815 A>T、-782 G>T、-638 insTC、-267 C>G和-219 del10bp。两个变异显示出体外功能效应。与-782G等位基因相比，-782T等位基因显示出较低的蛋白质结合亲和力和较低的启动子活性，然而，-815T等位基因显示出较高的蛋白质结合亲和力和较高的启动子活性。-782T变异被鉴定为乳腺癌和结直肠癌的风险等位基因（分别为OR，1.59；95% CI，1.06 - 2.34和OR，2.21；95% CI，1.22 - 3.99）。
鉴于其体外功能意义和发生率，ERBB4 -782 G>T多态性是乳腺癌和结直肠癌的一个风险因素。
