Genetic variants in VEGF gene family enhance colorectal cancer susceptibility via modulating metabolic pathways.

The genes belonging to vascular endothelial growth factor (VEGF) family played critical roles in tumor angiogenesis and the activation of signaling pathways associated with cancer promotion. However, it remains unclear whether genetic variants within VEGF gene family could influence the development of colorectal cancer. Here, we utilized the genotyping data from 1150 colorectal cancer patients and 1342 healthy controls to evaluate the associations between single nucleotide polymorphisms (SNPs) within VEGF gene family and the risk of colorectal cancer. Notably, the C allele of VEGFA rs6899540 was significantly associated with an increased colorectal cancer risk after false discovery rate (FDR) adjustment [odds ratio (OR) = 1.61, 95% confidence interval (CI): 1.25-2.06, P = 1.80 × 10; P = 0.015]. Furthermore, rs6899540 (A > C) could enhance VEGFA expression and exacerbate malignant phenotypes in colorectal cancer cells, as demonstrated through multiple biological experiments. Intriguingly, an integrated analysis using weighted gene co-expression network analysis (WGCNA) indicated that increased VEGFA expression may influence metabolic pathways, thereby increasing the risk of developing colorectal cancer. In conclusion, our findings demonstrated that genetic variants in VEGF family significantly contributed to susceptibility to colorectal cancer, which could provide new mechanistic insights into the molecular pathogenesis of colorectal cancer.