Vascular Endothelial Growth Factor Genotypes, Haplotypes, Gender, and the Risk of Non–Small Cell Lung Cancer

Abstract

Purpose: The vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving tumor growth and metastasis. Polymorphisms in the VEGF gene may regulate VEGF production. In this large case-control study, we investigated whether functional polymorphisms (−460C/T, +405C/G, +936C/T) in the VEGF gene are associated with the risk of non–small cell lung cancer (NSCLC). Experimental Design:VEGF genotypes and haplotypes were determined in 1,900 Caucasian patients with NSCLC and 1,458 healthy controls. The results were analyzed using logistic regression models, adjusting for age, gender, smoking status, pack-years of smoking, and years since smoking cessation (for ex-smokers). The false-positive report probability was estimated for the observed odds ratios (OR). Results: There were no overall associations between individual VEGF genotypes and the risk of NSCLC. Stratified analysis suggested that the combined +405CC+CG genotype was significantly associated with increased risk of lung adenocarcinoma in males (adjusted OR, 1.40; 95% confidence interval, 1.03-1.87). In haplotype analysis, haplotypes were globally associated with differences between cases and controls in males (P = 0.03). Specifically, the −460T/+405G/+936C haplotype was significantly (P = 0.02) associated with decreased risk of adenocarcinoma in males when compared with the most common CGC haplotype (adjusted OR, 0.76; 95% confidence interval, 0.50-0.98). None of the VEGF genotypes and haplotypes studied significantly influenced the susceptibility to NSCLC in females. Conclusions: Polymorphisms of −460C/T, +405C/G, and +936C/T in the VEGF gene do not play a major role in NSCLC risk. However, we could not exclude a minor role for the +405CC+CG genotypes and the 460T/+405G/+936C haplotype in lung adenocarcinogenesis in male Caucasians.

Vascular Endothelial Growth Factor Pathway Polymorphisms as Prognostic and Pharmacogenetic Factors in Cancer: A Systematic Review and Meta-analysis

“…VEGF þ405G>C is located in the 5 0 -untranslated region of the VEGF gene and is in modest linkage disequilibrium with VEGF þ936C>T (D 0 ¼ 0.65À0.74); this may help explain the nonsignificant trend found with VEGF þ936C>T (34,71). Genotype-phenotype analyses suggest that the C allele VEGF þ405G>C is associated with decreased promoter activity and decreased expression of VEGF, as the C allele reduces binding of the transcription factor, MZF1, which then subsequently reduces gene expression (72)(73)(74).…”

The allelic distribution of a single nucleotide polymorphism in the PDCD5 gene locus of Japanese non-small cell lung cancer patients

“…Several genetic polymorphisms are considered to be molecular markers that predict the risk, progression and prognosis of various cancers (3)(4)(5)(6)(7). Indeed, single nucleotide polymorphisms (SNPs) in several genes are reported to be associated with the risk of lung cancer (8)(9)(10), for example SNPs in the caspase-3 and vascular endothelial growth factor genes (11,12).…”

VEGF Gene Haplotypes Are Associated With Sarcoidosis

“…Our results suggest that there is a signifi cant correlation between SNPs in the VEGF, VEGFR-1, and VEGFR-2 genes and the onset and the course of sarcoidosis. As these pulmonary diseases, apart from neoplasia, 23,24 there are studies addressing the role of VEGFR in ARDS. 25 It was recently shown that genotypes and haplotypes of the VEGF gene are associated with lower VEGF plasma levels and higher mortality in patients with ARDS.…”