血管内皮生长因子（VEGF）变体及其受体相互作用与前列腺癌风险的关系。
Interaction among variant vascular endothelial growth factor (VEGF) and its receptor in relation to prostate cancer risk.
机构信息
Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky, USA.
出版信息
Prostate. 2010 Mar 1;70(4):341-52. doi: 10.1002/pros.21067.
BACKGROUND
Prostate cancer (PCa) incidence and mortality are disproportionately high among African-American (AA) men. Its detection and perhaps its disparities could be improved through the identification of genetic susceptibility biomarkers within essential biological pathways. Interactions among highly variant genes, central to angiogenesis, may modulate susceptibility for prostate cancer, as previous demonstrated. This study evaluates the interplay among three highly variant genes (i.e., IL-10, TGFbetaR-1, VEGF), their receptors and their influence on PCa within a case-control study consisting of an under-served population.
METHODS
This study evaluated single gene and joint modifying effects on PCa risk in a case-control study comprised of 859 AA men (193 cases and 666 controls) using TaqMan qPCR. Interaction among polymorphic IL-10, TGFbetaR-1 and VEGF was analyzed using conventional logistic regression analysis (LR) models, multi-dimensionality reduction (MDR) and interaction entropy graphs. Symbolic modeling allowed validation of gene-gene interaction findings identified by MDR.
RESULTS
No significant single gene effects were demonstrated in relation to PCa risk. However, carriers of the VEGF 2482T allele had a threefold increase in the risk of developing aggressive PCa. The presence of VEGF 2482T combined with VEGFR IVS6 + 54 loci were highly significant for the risk of PCa based on MDR and symbolic modeling analyses. These findings were substantiated by 1,000-fold cross validation permutation testing (P = 0.04), respectively.
CONCLUSION
These findings suggest the inheritance of VEGF and VEGFR IVS6 + 54 sequence variants may jointly modify PCa susceptibility through their influence on angiogenesis. Larger sub-population studies are needed to validate these findings and evaluate whether the VEGF-VEGR axis may serve as predictors of disease prognosis and ultimately clinical response to available treatment strategies.
背景
前列腺癌（PCa）在非裔美国人（AA）男性中的发病率和死亡率不成比例地高。通过确定重要生物学途径中的遗传易感性生物标志物，可能会改善其检测，甚至可能改善其差异。 以前已经证明，血管生成过程中的高度变异基因之间的相互作用可能会调节前列腺癌的易感性。本研究评估了三个高度变异基因（即 IL-10、TGFbetaR-1、VEGF）及其受体之间的相互作用及其在一项由服务不足人群组成的病例对照研究中对前列腺癌的影响。
方法
本研究使用 TaqMan qPCR 在一项由 859 名 AA 男性（193 例病例和 666 例对照）组成的病例对照研究中评估了单个基因和联合修饰对 PCa 风险的影响。使用传统的逻辑回归分析（LR）模型、多维降维（MDR）和相互作用熵图分析了多态性 IL-10、TGFbetaR-1 和 VEGF 之间的相互作用。符号建模允许验证 MDR 确定的基因-基因相互作用发现。
结果
没有发现单个基因与 PCa 风险相关的显著影响。然而，VEGF 2482T 等位基因的携带者患侵袭性 PCa 的风险增加了三倍。基于 MDR 和符号建模分析，VEGF 2482T 与 VEGFR IVS6 + 54 位点的存在对 PCa 的风险具有高度显著意义。这些发现分别通过 1000 倍交叉验证置换检验得到证实（P = 0.04）。
结论
这些发现表明，VEGF 和 VEGFR IVS6 + 54 序列变异的遗传可能通过其对血管生成的影响共同修饰 PCa 的易感性。需要更大的亚人群研究来验证这些发现，并评估 VEGF-VEGR 轴是否可以作为疾病预后的预测因子，最终是否可以作为现有治疗策略的临床反应的预测因子。
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