Association of polymorphisms of angiogenesis genes with breast cancer.
BACKGROUND
Few studies have systematically explored a pathway approach: to test the association of multiple polymorphisms from multiple genes important to angiogenesis simultaneously with risk of breast cancer. We report our preliminary data evaluating the association of polymorphisms from seven genes known to influence angiogenesis with the likelihood of having breast cancer.


METHODS
We recruited 715 controls and 520 subjects with breast cancer. Subjects provided a blood specimen and completed a questionnaire that included common breast cancer risk factors and breast cancer status. We evaluated candidate polymorphisms in the following genes: Hypoxia Inducible Factor-1 alpha (HIF1alpha), Vascular Endothelial Growth Factor (VEGF), VEGF Receptor 1 (VEGFR-1), VEGFR-2, endothelial Nitric Oxide Synthase (eNOS), Neuropilin-1 (NRP-1) and Neuropilin-2 (NRP-2). Testing for associations between each polymorphism and the presence or absence of breast cancer was performed.


RESULTS
VEGF-2578 AA and -1498 CC genotypes were more common in cancer cases than controls (P = 0.06 and P = 0.04, respectively). These two genotypes remained significant predictors of breast cancer status after adjusting for non-genetic risk factors estimated by the Gail model (P = 0.03 and P = 0.03, respectively). When comparing women with invasive versus pre-invasive breast cancer, the eNOS-786 TT and eNOS 894 GG genotypes were associated with a greater likelihood of invasive disease and the eNOS 894 GG genotype was associated with a greater likelihood of having metastatic disease.


CONCLUSIONS
There is an association of the VEGF-2578A and -1498C alleles with increased breast cancer risk. This association remains significant when adjusted for Gail score-related risk factors.
Schneider
Bryan P
BP
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. bpschnei@iupui.edu
Radovich
Milan
M
Sledge
George W
GW
Robarge
Jason D
JD
Li
Lang
L
Storniolo
Anna M
AM
Lemler
Suzanne
S
Nguyen
Anne T
AT
Hancock
Bradley A
BA
Stout
Michael
M
Skaar
Todd
T
Flockhart
David A
DA
D000328:Adult; D001741:Black or African American; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics*; D039942:Neuropilin-1 / Q000235:genetics; D039943:Neuropilin-2 / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D044465:White People
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039943:Neuropilin-2; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D052250:Nitric Oxide Synthase Type III; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2