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

Authors' Affiliations: Departments of ¹ Environmental Health, ² Hematology-Oncology, and ³ Medicine and Medical Biophysics, Princess Margaret Hospital/Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada; ⁴ Surgery and ⁵ Biostatistics, Harvard School of Public Health, Boston, Massachusetts; and ⁶ Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Requests for reprints: David C. Christiani, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. Phone: 617-432-1641; Fax: 627-432-6981; E-mail: dchris{at}hsph.harvard.edu.

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.

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