Association between five polymorphisms in vascular endothelial growth factor gene and urinary bladder cancer risk: A systematic review and meta-analysis involving 6671 subjects

Highlights

• Rs3025039, rs833052 and rs25648 polymorphisms increased BCa risk.

• Rs699947 A-allele should be a protective factor for MIBC.

Abstract

Background

Vascular endothelial growth factor (VEGF) gene plays a key role in angiogenesis and tumor growth. The relationship between VEGF gene polymorphisms and bladder cancer (BCa) risk was studied extensively in recent years. However, the currently available results are controversial. To ascertain whether VEGF polymorphisms are associated with the susceptibility to BCa, we conducted this systematic review and meta-analysis.

Materials and methods

Relevant studies were collected systemically from PubMed, Medline, Embase, Web of Science databases and the Cochrane Library. Odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated using random or fixed effects models by Stata statistical software. This systematic review protocol was registered at International prospective register of systematic reviews (PROSPERO) under number CRD42018099279.

Results

A total of eight articles including twenty case-control studies with 3206 BCa cases and 3645 controls were enrolled for this meta-analysis. By pooling all eligible studies, we found that rs3025039, rs833052 and rs25648 polymorphisms were significantly associated with BCa risk. However, in subgroup analyses by stage, we identified a decreased association between the rs699947 A-allele and Muscle-invasive Bladder Cancer (MIBC) under allele contrast, homozygous and recessive genetic models (A vs C: OR = 0.76; AA vs CC: OR = 0.49, 95%CI = 0.27–0.90, I² = 0.0%, P = 0.021; AA vs CA + CC: OR = 0.60, 95%CI = 0.38–0.96, I² = 0.0%, P = 0.034). As to ethnicity subgroup analysis, rs699947 and rs3025039 polymorphisms were thought as a risk factor for BCa risk in Asian population, while a decreased association was revealed between rs699947 (C > A) A-allele and BCa risk in African population under dominant, recessive, homozygous, heterozygous and allele contrast genetic models. While for other polymorphisms, null results were found.

Conclusion

Our meta-analysis suggested that rs3025039 (C > T), rs833052 (C > A) and rs25648 (C > T) polymorphisms of VEGF gene increased susceptibility to BCa risk. And our study also demonstrated homozygous TT genotype in rs3025039, homozygous AA genotype in rs833052 and homozygous TT genotype in rs25648 were significantly relevant to elevated BCa risk. In the meanwhile, it is worth noting that rs699947 (C > A) A-allele should be thought as a protective factor for MIBC.

Introduction

It is now acknowledged that bladder cancer (BCa) is the ninth most common frequently-diagnosed cancer and the most common urinary tract malignancy worldwide, with an estimated 165,000 deaths recorded and 430,000 new cases diagnosed in 2012 (Torre et al., 2015; Antoni et al., 2017). Incidence rates were consistently higher in males than females. A strong male predominance is observed that three quarters of all BCa patients occurred in men (Ferlay et al., 2010). Some risk factors are established to contribute to BCa risk. First, tobacco smoking was thought as a major risk factor, with a three times higher risk in smokers compared to non-smokers (Zeegers et al., 2004; Sanli et al., 2017). In addition, exposure to aromatic amines and other carcinogens through certain occupations was also reported as a contributor to BCa risk (Cantor et al., 2010; Letašiová et al., 2012). However, only a few of the exposed individuals finally develop BCa in their lifetime. This suggested that BCa risk was not only associated with potency and intensity of exposure to carcinogens, genetic factors may also play a critical role in BCa susceptibility (Volanis et al., 2010; Zheng et al., 2011).

Vascular endothelial growth factor (VEGF) gene plays an important role in BCa (Sakamoto et al., 2008; Goel and Mercurio, 2013). VEGF-mediated signaling contributes to key aspects in the tumor microenvironment, including the function of cancer stem cells and tumor initiation (Goel and Mercurio, 2013). VEGF can be induced and upregulated by other signaling effectors such as transforming growth factors and platelet derived growth factor (Lara et al., 2004) and its functions are mediated through two tyrosine kinase receptors, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, in vascular endothelial cells (de Vries et al., 1992; Millauer et al., 1993; Hanahan, 1997). In addition, compelling data indicated that VEGF signaling promotes the function of cancer stem cells and sustains their self-renewal through CD4⁺ Foxp3⁺ regulatory T cells which suppress an antitumor immune response in tumor growth, independent of its contribution to angiogenesis (Hansen et al., 2012).

The VEGF genes including VEGFA, VEGFB, VEGFC, and VEGFD are located on 6p21.1, 11q13.1, 4q34.3, and Xp22.2 respectively on the chromosome. And its receptors containing VEGFR1, VEGFR2, VEGFR3, and Neuropilin1 (NRP1) and NRP2 are located on 13q12.3, 4q12, 5q35.3, 10p11.22, and 2q33.3 respectively on the chromosome. As targeted therapy in urologic neoplasms developed rapidly nowadays (Mattei et al., 2014; Tsimberidou, 2015), VEGFR kinase inhibitor has become an excellent representative in targeted therapy and VEGF signaling provides a promising opportunity for the development of therapeutic approaches in cancers (Pasqualetti et al., 2007; Sakamoto et al., 2008; Du et al., 2009; Liang et al., 2014). With the advent of precision medicine, the role of single nucleotide polymorphism (SNP) in targeted therapy will be paid more and more attention.

Recently, a number of investigations on the relationship between VEGF gene polymorphisms and BCa risk have been performed (Kim et al., 2005; García-Closas et al., 2007; Henríquez-Hernández et al., 2012; Jaiswal et al., 2013; Wang et al., 2013; Yang et al., 2014; Fu et al., 2017; Ben Wafi et al., 2018). Among these polymorphisms, rs3025039 (C > T), rs699947 (C > A), rs833061 (C > T), rs833052 (C > A) and rs25648 (C > T) have been widely investigated for their potential effect on BCa risk. However, inconsistent results were concluded and the small sample size of cases with BCa in studies weakens the strength of evidence.

Hence, we performed this systematic review and meta-analysis of currently available articles to evaluate firstly the possible associations between VEGF gene polymorphisms with BCa risk and secondly to evaluate the associations after stratification by clinicopathological staging and ethnicity.