Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk.

Insulin-like growth factor (IGF) 1 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 single nucleotide polymorphisms in 1173 cases and 1201 controls from the New England Case-Control (NECC) study and 296 cases and 854 controls from the Nurses' Health Study (NHS). The association of haplotypes and single nucleotide polymorphisms (SNPs) with ovarian cancer was estimated using unconditional (NECC) and conditional (NHS) logistic regression. Additionally, we evaluated the association of SNPs with IGF1, IGF-binding protein (IGFBP) 3 and IGFBP2 plasma levels (n = 380 NHS controls). Our data suggest a decreased risk for women carrying haplotype 2C of the IGF1 gene [odds ratios (ORs) = 0.82, 95% confidence intervals (CIs) = 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 IGFBPs (rs10228265, rs4988515 and rs2270628) were associated with increased ovarian cancer risk, and several IGF1 (rs11111285, rs1996656 and rs1019731) and IGFBP3 (rs2270628, rs2854746 and 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.