Abstract
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.
Highlights
Prostate cancer accounts for 29% of cancer incidence and 9% of cancer deaths and it is the most common cancer and the second leading cause of cancer death in American men in 2012 [1]
In the Cancer Genetic Markers of Susceptibility (CGEMS) group, we evaluated the main effect of 2,651 angiogenesis single nucleotide polymorphisms (SNPs) associated with prostate cancer aggressiveness status using logistic regression models
Besides the CGEMS identified SNP-SNP interactions, we explored whether other SNP interactions in the identified gene pairs in the Moffitt group were significantly associated with prostate cancer aggressiveness
Summary
Prostate cancer accounts for 29% of cancer incidence and 9% of cancer deaths and it is the most common cancer and the second leading cause of cancer death in American men in 2012 [1]. Prostate cancer has a substantial clinical heterogeneity. Physicians often have difficulty distinguishing between patients who will develop indolent and aggressive tumors at the time of a prostate cancer diagnosis [2]. For prostate cancer patients with a low risk, conservative management and treatment are recommended because an indolent course over a long period of time may be observed. Several features (such as prostate specific antigen, clinical stage and tumor grade) have been used to classify high-risk patients who need immediate therapy and the low risk patients who need conservative treatment. When using the existing features, approximately 20% of these low-risk prostate cancer patients died due to conservative treatment [3]. There is an urgent need for identifying biomarkers in order to improve prediction accuracy of prostate cancer aggressiveness
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