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Carcinogenesis Advance Access published online on October 25, 2009
Carcinogenesis, doi:10.1093/carcin/bgp257
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Common Genetic Variation in IGF1, IGFBP1, and IGFBP3 and Ovarian Cancer Risk

Kathryn L. Terry1,3, Shelley S. Tworoger2,3, Margaret A. Gates2,3, Daniel W. Cramer1,3 and Susan E. Hankinson2,3

1 Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA
2 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
3 Department of Epidemiology, Harvard School of Public Health, Boston, MA

Corresponding author: Kathryn Terry Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115; Phone: 617-732-4895, Fax: 617-732-4899; Email: kterry{at}partners.org

IGF1 and its binding proteins foster cellular proliferation and inhibit apoptosis. In vitro studies show that IGF1 increases ovarian cell growth and invasive potential, suggesting a role for the IGF1 pathway in ovarian cancer etiology. We evaluated genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to ovarian cancer risk by genotyping 29 haplotype-tagging SNPs in 1173 cases and 1201 controls from the New England Case Control Study (NECC) and 296 cases and 854 controls from the Nurses’ Health Study (NHS). The association of haplotypes and SNPs with ovarian cancer was estimated using unconditional (NECC) and conditional (NHS) logistic regression. Additionally, we evaluated the association of SNPs with IGF1, IGFBP3, and IGFBP2 plasma levels (n = 380 NHS controls). Our data suggest a decreased risk for women carrying haplotype 2C of the IGF1 gene (OR = 0.82, 95% CI = 0.69-0.98), and an increased risk for women carrying haplotype 1D (OR = 1.41, 95% CI = 1.03-1.94) or 2D (OR = 1.20, 95% CI = 1.01-1.41) in the binding proteins. When evaluated individually, three SNPs in the IGF binding proteins (rs10228265, rs4988515, rs227062) were associated with increased ovarian cancer risk, and several IGF1 (rs11111285, rs1996656, rs1019731) and IGFBP3 (rs2270628, rs2854746, rs2854744) SNPs were significantly associated with IGF1, IGFBP3, and IGFBP2 plasma levels. Some haplotypes and SNPs in the IGF pathway genes may be associated with ovarian cancer risk; however, these results need to be confirmed. Of particular interest was the IGFBP3 SNP rs2270628 which was associated with both increased IGF1 plasma levels and higher ovarian cancer risk.

Key Words: IGF1 • IGFBP1 • IGFBP3 • ovarian cancer

Received April 22, 2009; revised October 15, 2009; accepted October 17, 2009.


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