Interaction among variant vascular endothelial growth factor (VEGF) and its receptor in relation to prostate cancer risk

Abstract

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, TGFβR-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, TGFβR-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.

IL-10 polymorphisms and prostate cancer risk: a meta-analysis

“…As a result, there were 10 studies retrieved on the basis of the above search criteria for PCa susceptibility related to IL-10 À1082 A4G, À819 C4T and À592 C4A polymorphisms. 9,[16][17][18][19][20][21][22][23][24] The main study characteristics are summarized in Table 1. There were three studies of subjects of Asian descent 20,22,24 and seven studies of subjects of Caucasian descent.…”

“…There were three studies of subjects of Asian descent 20,22,24 and seven studies of subjects of Caucasian descent. 9,[16][17][18][19]21,23 Among these studies, three studies have investigated only one SNP (McCarron et al considered -1082 A4G; Eder et al considered -592 C4A; and Omrania et al considered À1082 A4G), whereas three studies included two SNPs (Michaud et al considered À1082 A4G and À819 C4T; Wang et al considered À1082 A4G and À592 C4A; and Kesarwani et al considered À1082 A4G and À819 C4T). The remaining four studies included three SNPs.…”

“…A classical PCRrestriction fragment length polymorphism assay was conducted in two studies, 16,24 a TaqMan assay was used in five studies, 9,18,19,21,23 and an amplification refractory IL-10 polymorphisms and prostate cancer risk N Shao et al mutation system-PCR technique assay was used in two studies. 17,22 The last study adopted allele-specific oligonucleotide-PCR method.…”

Common Polymorphisms in Angiogenesis

“…However, in BRCA1 carriers the low-VEGF T-allele confers protection from disease (Jakubowska et al 2008). Similarly, although large case-control studies have failed to find an association between prostate cancer risk and VEGF polymorphisms (Jacobs et al 2008), when gene-gene interactions are considered, several smaller studies have shown that VEGF polymorphisms can play a role in disease risk or aggressiveness (Sfar et al 2010; VanCleave et al 2010).…”

“…For example, the 2604C allele decreases transcriptional activity and protects against age-related macular degeneration (Galan et al 2010). In addition, there is evidence of genegene interactions with VEGF genotype ( VanCleave et al 2010). However, studies to identify VEGFR2 polymorphisms that might predict Lucentis response were negative (KloeckenerGruissem et al 2011).…”