IGF pathway gene variants and risk of endometrial cancer

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Insulin-like growth factor (IGF) family members have been implicated in cellular growth, differentiation, apoptosis, obesity and more recently, in endometrial cancer tumorigenesis. It is theorized that genetic variation in IGFpathway genes may modify the effect of known estrogenic and obesity related risk factors for endometrial cancer on disease etiology. We tested this hypothesis in a population-based case-control study of incident endometrial cancer by evaluating the individual and joint effects of endogenous markers of estrogen: body mass index (BMI), waist-hip ratio (WHR), and menstrual and reproductive factors with genetic susceptibility. A total of 23 haplotype-tagging single nucleotide polymorphisms (SNPs) were selected to capture common genetic variants in the IGF1, IGF2, IGFALS, and IGFBP3 genes. Included in the study were 1,007 cases and 991 controls who completed a questionnaire eliciting information about demographic and reproductive factors and were genotyped for polymorphisms in the IGF1, IGF2, IGFALS, and IGFBP3 genes Unconditional logistic regression was used to calculate odds ratios (OR’s) and 95% confidence intervals (CI) after adjusting for potential confounding factors. We found that the variant genotype (G/G) in the IGFALS promoter (rs344352) was significantly associated with a reduced risk of endometrial cancer (OR=0.72, 95% CI: 0.55-0.95). Furthermore, this association was more pronounced among women characterized by lower estrogen exposures including lower BMI (OR=0.58, 95% CI: 0.38-0.89), fewer years of menstruation (OR=0.64, 95% CI: 0.43-0.96), and who were post-menopausal (OR=0.56, 95% CI: 0.36-0.87). Several other SNPs in IGF1 (rs2946834, rs5742723, rs4764697), IGF2 (rs3802971), and IGFBP3 (rs2270628) were also found to be associated with altered endometrial cancer risk. We are in the process of conducting detailed analysis and will report the final results of the study at the AACR annual meeting. Taken together, these results suggest a role for common IGF pathway gene variants in altered endometrial cancer risk.