The association between plasma insulin-like-growth factor (IGF)-I and colorectal cancer is modified by BMI or C-peptide.

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Background: Accumulating evidence strongly supports a role of insulin-like growth factor (IGF)-I and insulin in promoting colorectal tumor growth. However, data to simultaneously assess the combined association of IGF-I and insulin with colorectal cancer risk are lacking. Methods: In a case-control study nested in the Physicians? Health Study of 14,916 U.S. men, data for baseline plasma levels of IGF-I, IGFBP-3 and C-peptide (a marker of insulin production and insulin resistance) were available among 158 colorectal cancer cases diagnosed during 13 years of follow-up and 269 age- and smoking-matched controls, all without baseline diabetes. We calculated BMI (kg/m2) according to baseline height and weight and assessed the molar ratio of IGF-I to its binding protein (IGFBP)-3 (IGF-I/IGFBP-3, an indicator of bioavailable IGF-I). Relative risks (RR) and 95% confidence intervals (CI) were calculated using conditional logistic regression analysis. Tertiles of BMI, IGF-I/IGFBP-3, and C-peptide were defined according to the distribution among controls. Results: In a multivariate model controlling for age, smoking, fasting status, and BMI, plasma levels of C-peptide, IGF-I, and IGFBP-3 were each statistically significantly associated with colorectal cancer risk. The association of IGF-I/IGFBP-3 with risk varied by C-peptide levels (Pinteraction=0.046). Among men with C-peptide in the lower 2 tertiles, we observed strong and linear associa tions between IGF-I/IGFBP-3 and colorectal cancer risk. However, we found no such associations among men in the highest tertile of C-peptide. The RRs for the lowest to the highest tertile of IGF-I/IGFBP-3 were: 1.0 (ref), 1.4, and 3.0 (95% CI: 1.1–8.1) among men with C-peptide in the lowest tertile; 1.8, 2.3, and 4.7 (95% CI: 1.7–13) among men with C-peptide levels in the middle tertile; and 3.6, 3.3, and 3.5 (95% CI: 1.2–10) among men with C-peptide levels in the highest tertile. Conversly, among men in the lowest tertile of IGF-I/IGFBP-3, we found a strong linear association for C-peptide (RRs from the lowest to the highest tertile: 1.0 (ref), 1.8, and 3.6 (95%CI: 1.3–10). Men with either high IGF-I/IGFBP-3 or high C-peptide levels had an over 3-fold increased risk of colorectal cancer. We observed a similar interaction between BMI and IGF-I/IGFBP-3 (Pinteraction=0.03). Conclusions: Our data suggest that either high insulin or high IGF-I could be sufficient to promote colorectal carcinogenesis. Men with high insulin or overweight were at higher risk regardless of their IGF-1 status, but in lean men or men with medium to low C-peptide levels, we found a strong and linear positive association between IGF-I and colorectal cancer.