Genetic variants of vascular endothelial growth factor predict risk and survival of gliomas

Abstract

The vascular endothelial growth factor regulates angiogenesis that is increased in glioma. VEGF polymorphisms are thought to modulate vascular endothelial growth factor plasma levels and therefore may be implicated in glioma risk. We aimed to clarify the role of VEGF and von Willebrand factor polymorphisms in glioma susceptibility and prognosis. A case-control study of 126 glioma patients and 180 cancer-free controls was performed. Using Sequenom MassARRAY platform, 11 VEGF and 1 VWF polymorphisms were genotyped. Unconditional multivariate logistic regression models were used to calculate odds ratios and 95% confidence intervals. The associations between polymorphisms and survival were evaluated using a Cox regression model. Bonferroni's adjustment was used to correct for multiple testing. The VEGF polymorphism rs833061 was strongly associated with increased risk for glioma (odds ratio = 164.85) and glioblastoma (odds ratio = 155.66), confirmed after Bonferroni correction. Also, the VEGF polymorphisms rs3024994, rs2010963, and particularly the homozygous carriers of rs1005230 were associated with a worse prognosis for glioma and glioblastoma. Our data support a role of VEGF and VWF polymorphisms as glioma biomarkers, with additional potential relevance for molecular stratification of patients for anti-angiogenic therapies.

Associations ofVEGFAandKDRsingle-nucleotide polymorphisms and increased risk and aggressiveness of high-grade gliomas

“…To the best of our knowledge, there is just one previous study focusing on the role of this SNP in risk of HGG. 26 Linhares et al did not demonstrate the association of VEGF –2578C/A with HGG in a significantly smaller population of GBM ( N = 84), which can be the reason for this result disparity, since the controls’ allele frequencies were similar in both populations. In fact, the association of −2578 CC or CA genotypes and increased risk of HGG was expected, since the “C” allele has been related to higher VEGFA production 19 and a higher risk of other tumors, such as lymphoma and multiple myeloma.…”

“…Regarding VEGFA –634G/C, our finding is in accordance with those previously reported from China, also demonstrating that the “C” allele was associated with an increased all-grade glioma risk, including HGG. 24,27,28 Linhares et al 26 also reported an increased risk of gliomas, grades II–IV in patients exhibiting the “T” allele from VEGFA 460C/T in Caucasians from Portugal. Knowing that the roles of “G” and “C” alleles of VEGFA –634G/C and “C” and “T” alleles of VEGFA –460C/T in VEGFA production are uncertain in the literature, 19,22 the results of this study and of those described above suggest that the “C” allele of VEGFA –634G/C and “T” allele of VEGFA –460C/T determine more VEGFA production, more blood vessel formation, and more susceptibility to HGG.…”

“…Regarding VEGFA-634G/C, our finding is in accordance with those previously reported from China, also demonstrating that the ''C'' allele was associated with an increased all-grade glioma risk, including HGG. 24,27,28 Linhares et al 26 also reported an increased risk of gliomas, grades II-IV in patients exhibiting the ''T'' allele from VEGFA 460C/ T in Caucasians from Portugal. Knowing that the roles OR: odds ratio adjusted by age and gender; CI: confidence interval; VEGFA: vascular endothelial growth factor A; KDR: vascular endothelial growth receptor 2.…”

“…A meta-analysis of genome-wide association studies identified specific differences in genetic susceptibility for GBM and non-GBM tumors, but the SNPs enrolled in this study were not cited by the authors. 23 There are only few studies focusing the association of VEGFA 24–28 and KDR 25,29,30 SNPs with risk of developing HGG, and VEGFA 26,27 and KDR 29,30 SNPs with clinicopathological aspects of HGG patients. None of these previous studies were conducted exclusively in HGG, and, except for Linhares et al, 26 who evaluated pure Caucasian Europeans, all studies were conducted only in Chinese.…”

Association of VEGFA polymorphisms with chronic obstructive pulmonary disease in Chinese Han and Mongolian populations

“…Besides, haplotypes with rs833070 were found to predict the risk of progression to nodular goiter, papillary thyroid carcinoma, acute mountain sickness, recurrent spontaneous miscarriage, vaso-occlusive crisis, preeclampsia and type 2 diabetes (Al-Habboubi et al, 2012;Almawi et al, 2013;Ding et al, 2011;Liu et al, 2017;Sellami et al, 2018). The VEGF polymorphism rs3024994 was discerned to be associated with non-squamous histology and a poor prognosis for glioma and glioblastoma (de Mello et al, 2013;Linhares et al, 2018). SNP rs3024997 was observed to be associated with the treatment effect of wet age-related macular degeneration and an increased risk of papillary thyroid carcinoma and nodular goiter (Boltz et al, 2012;Liu et al, 2017).…”