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Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and Prognosis

Authors' Affiliations: ¹ Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden, ² Division of Molecular Genetic Epidemiology, German Cancer Research Center and ³ Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany, ⁴ Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University and ⁵ Department of Oncology, Norrlands University Hospital, Umeå, Sweden, ⁶ Department of Tumor Biology, ⁷ I Clinics of Radiotherapy, and ⁸ Clinics of Chemotherapy, Centre of Oncology, Maria Sklodowska-Curie Institute, Gliwice, Poland

Requests for reprints: Qianren Jin, Department of Biosciences at Novum, Karolinska Institute, SE-141 57, Huddinge, Sweden. Phone: 46-8-608-9238; Fax: 46-8-608-1501; E-mail: qianren.jin{at}cnt.ki.se.

Purpose: Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphisms in the VEGF gene with breast cancer risk and prognostic characteristics of the tumors in a large case-control study.

Experimental Design: We examined three polymorphisms in the VEGF gene (–2578C/A, –1154G/A, and +936C/T) in 571 familial breast cancer cases from Poland and Germany and –2578C/A, –634G/C, and +936C/T polymorphisms in 974 unselected breast cancer cases from Sweden together with ethnically and geographically selected controls.

Results: None of the polymorphisms or any haplotype was significantly associated with either familial or unselected breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the unselected cases for genotypes or haplotypes that associated with tumor characteristics. The –634CC genotype and the –2578/–634 CC haplotype were significantly associated with high tumor aggressiveness (large tumor size and high histologic grade, P < 0.01) and the –2578AA genotype and the –2578/–634 AG haplotype with low histologic grade tumors (P = 0.04). The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status.

Conclusions: Although none of the polymorphisms studied in the VEGF gene was found to influence susceptibility to breast cancer significantly, some of the VEGF genotypes and haplotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.

Key Words: VEGF • genotype • haplotype • case-control study

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