Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and Prognosis

Abstract

Purpose: Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphisms in the VEGF gene with breast cancer risk and prognostic characteristics of the tumors in a large case-control study. Experimental Design: We examined three polymorphisms in the VEGF gene (−2578C/A, −1154G/A, and +936C/T) in 571 familial breast cancer cases from Poland and Germany and −2578C/A, −634G/C, and +936C/T polymorphisms in 974 unselected breast cancer cases from Sweden together with ethnically and geographically selected controls. Results: None of the polymorphisms or any haplotype was significantly associated with either familial or unselected breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the unselected cases for genotypes or haplotypes that associated with tumor characteristics. The −634CC genotype and the −2578/−634 CC haplotype were significantly associated with high tumor aggressiveness (large tumor size and high histologic grade, P < 0.01) and the −2578AA genotype and the −2578/−634 AG haplotype with low histologic grade tumors (P = 0.04). The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Conclusions: Although none of the polymorphisms studied in the VEGF gene was found to influence susceptibility to breast cancer significantly, some of the VEGF genotypes and haplotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.

Influence of VEGF‐A gene variation and protein levels in breast cancer susceptibility and severity

“…12 In a large recently reported study involving 572 familial breast cancer cases, 974 unselected breast cancer cases and 974 controls, the 22578C > A, 21154G > A, 2634G > C and the 936C > T VEGF polymorphisms were studied. 13 Although none of the 3 polymorphisms or their haplotypes were associated with disease susceptibility, the 2634 CC genotype and the 22578/2634 CC haplotype were significantly associated with large high-grade tumours and the 22578AA genotype and the 22578/2634AG haplotype with low-grade tumours. 13 In another recent study of 3 VEGF polymorphisms (2460C > T, 1405G > C and 936C > T) and their role in breast cancer survival, the 1405G allele was associated with decreased overall survival.…”

“…13 Although none of the 3 polymorphisms or their haplotypes were associated with disease susceptibility, the 2634 CC genotype and the 22578/2634 CC haplotype were significantly associated with large high-grade tumours and the 22578AA genotype and the 22578/2634AG haplotype with low-grade tumours. 13 In another recent study of 3 VEGF polymorphisms (2460C > T, 1405G > C and 936C > T) and their role in breast cancer survival, the 1405G allele was associated with decreased overall survival. 14 The study also showed that the 2460C/1405G/936T haplotype was associated with increased survival.…”

“…13 However, the 2460T/1405C/27C/936C haplotype may be associated with reduced breast cancer risk. This suggests that haplotypes rather than individual SNPs may influence disease susceptibility and need to be evaluated further in large cohorts.…”

“…11 Some recent studies have not identified any association between breast cancer and some VEGF polymorphisms, which include 21154 A/G, 12,13 22578C/A, 2634G/C and 1936C/T. 13 In contrast however, other studies have demonstrated that the 2460 C/T and 1405 G/C polymorphisms are associated with breast cancer survival 14 and 2634G/C, 22578C/A and 21154 A/G are associated with breast cancer prognosis. 12,13 The current study aims to evaluate the role of regulatory VEGF polymorphisms (2460C > T, 1405G > C, 27C > T in the 5 0 UTR and 936C > T in 3 0 UTR) and haplotypes in influencing breast cancer susceptibility and severity, blood VEGF levels and VEGF protein expression in breast cancer.…”

Vascular Endothelial Growth Factor (VEGF) Gene Polymorphisms and Breast Cancer Risk in a Chinese Population

“…A population-based case-control study conducted in urban Shanghai, China from 1996 to 1998, suggested that the VEGF C936T polymorphism might be a susceptibility factor for breast cancer among Chinese women (Kataoka et al, 2006). A large case-control study found that the VEGF -634CC genotype and the VEGF -2578/-634 CC haplotype were significantly associated with high tumor aggressiveness (large tumor size and high histologic grade) and the VEGF -2578AA genotype and the VEGF -2578/-634 AG haplotype with low histologic grade tumors (Jin et al, 2005). A large case-control study in 500 women with breast cancer and 500 sex-and age-matched healthy control subjects found that carriers of a VEGF 936T-allele are at decreased risk for breast cancer in Austria (Krippl et al, 2003).…”