Association of VEGF gene polymorphisms and breast cancer susceptibility: An updated systematic review and metaanalysis

Abstract

Breast cancer is among the most common malignancies in women worldwide, with genetic predispositions and environmental factors. Low-penetrance genes such as breast cancer (BRCA)1 and BRCA2 have been identified with implications in breast cancer susceptibility. Vascular endothelial growth factor (VEGF) polymorphisms that code for the VEGF protein play an important part in carcinogenesis by modulating 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 cancer risk. Despite inconsistencies in many results due to small sample sizes and methodological differences, this study aimed to clarify the associations between VEGF polymorphisms and breast cancer risk by conducting a meta-analysis. A systematic review and meta-analysis were performed and reported in accordance with the PRISMA 2020 guidelines. Twenty-five eligible articles contributed 53 polymorphismspecific case–control datasets that included five VEGF polymorphisms. Statistical analyses were performed using Metagenyo software, and the results revealed a significant association. 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 revealed that Asian populations are more susceptible than Caucasians in the overall five polymorphisms. The 405 C > G polymorphism exhibited significance in the dominant and over-dominant models. In the sensitivity analysis, all the effects remained the same except for 405 C > G, which was influenced by a single study. The publication bias was low in all the data. The findings of the present study suggest that VEGF polymorphisms may serve as population-specific genetic biomarkers for breast cancer risk stratification. These variants may also help identify patient subgroups that are more likely to benefit from VEGF-targeted or other anti-angiogenic therapies by influencing VEGF expression and angiogenic activity. However, their clinical utility for treatment selection and prediction of therapeutic response requires validation in larger, ethnically diverse cohorts and in prospective pharmacogenomic studies.