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Chulalongkorn Medical Journal

Abstract

Breast cancer is among the most common malignancies in women worldwide with genetic predispositions and environmental factors and identified low-penetrance genes such as BRCA1 and BRCA2 with implications in breast cancer susceptibility. Vascular endothelial growth factor polymorphisms of VEGF coding for VEGF protein that plays an important part in carcinogenesis through angiogenesis required for tumor growth, invasion, and metastasis. There are five polymorphisms associated with the VEGF gene; 936 C > T, 2578 C > A, 634 G > C, 460 T > C, and 405 C > G which have been linked to altered risks in cancer. Despite inconsistency in many results ascribed to small sample sizes and method analysis difference, this study aimed to provide clarify by conducting a meta-analysis to determine the associations between VEGF polymorphisms and breast cancer risk. A systematic review and meta-analysis was conducted and reported in accordance with the PRISMA 2020 guidelines. Twenty-five eligible articles contributed 53 polymorphism-specific case–control datasets involving five VEGF polymorphisms. Statistical analyses were also performed using Metagenyo software. The results revealed a significant association in the analysis. The 2578 C > A and 460 T > C polymorphisms were associated with increased risks while 936 C > T and 634 G > C were not. Subgroup analyses also demonstrated that Asian populations are more susceptible than Caucasians in the overall five polymorphisms. The 405 C > G showed significant in a dominant and over-dominant model. In sensitivity analysis, all the effects remained the same except for the 405 C > G, which was impacted by a single study influence. The publication bias was low in all the data. Present study findings suggest that VEGF polymorphisms may serve as population-specific genetic biomarkers for breast cancer risk stratification. By influencing VEGF expression and angiogenic activity, these variants may also help identify patient subgroups that are more likely to benefit from VEGF-targeted or other anti-angiogenic therapies. However, their clinical utility for treatment selection and prediction of therapeutic response requires validation in larger, ethnically diverse cohorts and prospective pharmacogenomic studies.

DOI

10.56808/2673-060X.5834

First Page

Breast cancer remains one of the most prevalent malignancies affecting women worldwide. (1) Its development is driven by a complex interplay of genetic predisposition and environmental influences. While high-penetrance genes such as BRCA1 and BRCA2 significantly increase risk in hereditary cases, numerous low-penetrance variants, together with lifestyle and environmental exposures, also contribute to overall susceptibility. (2) Angiogenesis, the formation of new blood vessels from existing vasculature is a fundamental biological process that supports tumor progression by supplying essential nutrients and oxygen. (3) This process is tightly regulated through a balance of proteolytic enzymes, angiogenic stimulators, and endogenous inhibitors. Among these regulators, vascular endothelial growth factor (VEGF) is recognized as a key mediator of angiogenesis. (4) Over expression of VEGF has been documented in multiple malignancies, including breast cancer, where it promotes tumor growth, invasion, and metastasis. Extensive studies have clarified the VEGF signaling pathway, reinforcing its critical role in pathological angiogenesis, tumor aggressiveness, and patient prognosis. (5) Given its biological importance, VEGF has emerged as an important target for anti-angiogenic therapies, and preclinical models have demonstrated the therapeutic potential of VEGF inhibition. Numerous single nucleotide polymorphisms (SNPs) identified within the VEGF gene are known to influence VEGF expression levels, thereby altering angiogenic activity. Several VEGF variants particularly 2578 C/A, 405 C/G, 460 T/C, 634 G/C, and 936 C/T have been widely investigated for their possible roles in modulating cancer susceptibility, tumor progression, and metastatic behavior. (6-8) Despite considerable research, relatively fewer studies have specifically evaluated the association between VEGF polymorphisms and breast cancer risk. Existing epidemiological findings have often been inconsistent, largely due to small sample sizes, limited statistical power, and variations in study design or genotyping quality. Our earlier meta-analysis also suffered from these constraints; the associations involving the 460 T>C and 405 C>G polymorphisms were particularly inconclusive due to insufficient sample sizes. (6) Since that time, several new studies with larger cohorts, improved genotyping methodologies, and more diverse populations have been published. These additions provide an essential opportunity to re-evaluate the evidence with greater statistical precision. Therefore, an updated meta-analysis was undertaken to enhance the robustness of conclusions, incorporate higher-quality datasets, and explore potential subgroup effects more comprehensively.

Last Page

This updated and comprehensive meta-analysis provides robust evidence that specific VEGF gene polymorphisms contribute to breast cancer susceptibility. Among the five variants evaluated, VEGF −2578 C/A, 460 T/C, and 405 C/G demonstrated significant associations with increased risk under various genetic models, suggesting that these loci may influence VEGF expression and thereby modulate angiogenic activity central to breast tumor development. In contrast, VEGF 936 C/T and 634 G/C showed no meaningful association with disease risk, indicating that their biological contribution to breast carcinogenesis may be limited or context dependent. Ethnicity emerged as an important modifier of genetic risk, with Asian populations showing stronger associations than Caucasian groups across several VEGF variants. These findings underscore the relevance of population-specific genetic architecture and the necessity for diverse representation in cancer genetics research. However, the paucity of data from African populations remains a notable gap and restricts the generalizability of conclusions for these groups. Despite some heterogeneity among studies, rigorous sensitivity analyses, large pooled sample sizes, and low publication‐bias indicators strengthen the credibility of the present findings. Collectively, this meta-analysis enhances current understanding of VEGF-mediated genetic susceptibility to breast cancer and highlights the importance of integrating angiogenesis-related genetic markers into future risk prediction models. To further clarify VEGF’s role, large, multi-ethnic, well-characterized cohort studies with standardized genotyping approaches are strongly recommended.

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