Department of Biostatistics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America.
PLoS One. 2013 Apr 3;8(4):e59688. doi: 10.1371/journal.pone.0059688. Print 2013.
Angiogenesis has been shown to be associated with prostate cancer development. The majority of prostate cancer studies focused on individual single nucleotide polymorphisms (SNPs) while SNP-SNP interactions are suggested having a great impact on unveiling the underlying mechanism of complex disease. Using 1,151 prostate cancer patients in the Cancer Genetic Markers of Susceptibility (CGEMS) dataset, 2,651 SNPs in the angiogenesis genes associated with prostate cancer aggressiveness were evaluated. SNP-SNP interactions were primarily assessed using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM) approach in the CGEMS group, and were then re-evaluated in the Moffitt group with 1,040 patients. For the identified gene pairs, cross-evaluation was applied to evaluate SNP interactions in both study groups. Five SNP-SNP interactions in three gene pairs (MMP16+ ROBO1, MMP16+ CSF1, and MMP16+ EGFR) were identified to be associated with aggressive prostate cancer in both groups. Three pairs of SNPs (rs1477908+ rs1387665, rs1467251+ rs7625555, and rs1824717+ rs7625555) were in MMP16 and ROBO1, one pair (rs2176771+ rs333970) in MMP16 and CSF1, and one pair (rs1401862+ rs6964705) in MMP16 and EGFR. The results suggest that MMP16 may play an important role in prostate cancer aggressiveness. By integrating our novel findings and available biomedical literature, a hypothetical gene interaction network was proposed. This network demonstrates that our identified SNP-SNP interactions are biologically relevant and shows that EGFR may be the hub for the interactions. The findings provide valuable information to identify genotype combinations at risk of developing aggressive prostate cancer and improve understanding on the genetic etiology of angiogenesis associated with prostate cancer aggressiveness.
血管生成已被证明与前列腺癌的发展有关。大多数前列腺癌研究都集中在单个单核苷酸多态性（SNP）上，而 SNP-SNP 相互作用被认为对揭示复杂疾病的潜在机制有很大影响。利用癌症遗传易感性基因标记（CGEMS）数据集的 1151 名前列腺癌患者，评估了与前列腺癌侵袭性相关的血管生成基因中的 2651 个 SNP。在 CGEMS 组中，主要使用两阶段随机森林加多变量自适应回归样条（TRM）方法评估 SNP-SNP 相互作用，并在 Moffitt 组的 1040 名患者中重新进行评估。对于确定的基因对，应用交叉评估来评估两个研究组中的 SNP 相互作用。在两个组中，都鉴定到三个基因对（MMP16+ROBO1、MMP16+CSF1 和 MMP16+EGFR）中的五个 SNP-SNP 相互作用与侵袭性前列腺癌有关。在 MMP16 和 ROBO1 中存在三对 SNP（rs1477908+rs1387665、rs1467251+rs7625555 和 rs1824717+rs7625555），在 MMP16 和 CSF1 中存在一对 SNP（rs2176771+rs333970），在 MMP16 和 EGFR 中存在一对 SNP（rs1401862+rs6964705）。结果表明 MMP16 可能在前列腺癌侵袭性中发挥重要作用。通过整合我们的新发现和现有的生物医学文献，提出了一个假设的基因相互作用网络。该网络表明，我们鉴定的 SNP-SNP 相互作用具有生物学相关性，并表明 EGFR 可能是相互作用的枢纽。这些发现为识别具有侵袭性前列腺癌风险的基因型组合提供了有价值的信息，并加深了对与前列腺癌侵袭性相关的血管生成的遗传病因的理解。
