Background: Promoter hypermethylation of insulin-like growth factor binding protein (IGFBP) genes may link energy balance-related factors to colorectal cancer (CRC) risk. Other mechanisms that we explored were microsatellite instability (MSI), the CpG island methylator phenotype (CIMP) and chromosomal instability (CIN).

Methods: We determined IGFBP-2, -3, and -7 methylation, MSI, CIMP and CIN in 733 CRC cases identified between 1989 and 1993 within the Netherlands Cohort Study (NLCS; n=120,852). All NLCS participants self-reported determinants at baseline in 1986. Available information includes adult BMI, BMI at age 20, BMI change since age 20, height, adult trouser/skirt size, early life exposure to energy restriction and non-occupational physical activity. Using a case-cohort approach (n subcohort=5000), we estimated hazard ratios (HRs) for CRC according to the extent of IGFBP gene methylation and specific tumor instability type.

Results: Adult BMI, BMI change since age 20 and energy restriction in early life were associated with the risk of CRC with an increased methylated IGFBP gene number after multivariable adjustment. Comparison of the highest versus lowest BMI tertiles gave HRs [95% confidence intervals (CIs)] for CRCs with 0 (18.2%), 1 (28.9%), 2 (33.2%) and 3 (19.7%) methylated genes of 1.39 (0.88-2.20), 1.12 (0.77-1.62), 1.66 (1.16-2.36) and 2.05 (1.28-3.29), respectively. BMI change measured continuously was positively associated with the risk of having a CRC characterized by 2 methylated IGFBP genes (per 5-unit increase: HR=1.43, 95% CI: 1.09-1.87). Exposure to energy restriction during the Hunger Winter versus non-exposure gave HRs (95% CIs) for CRCs with 0, 1, 2 and 3 methylated genes of 1.01 (0.67-1.53), 1.03 (0.74-1.44), 0.72 (0.52-1.00) and 0.50 (0.32-0.78), respectively. Two other proxies for early life energy restriction corroborated this inverse relationship. Height, adult trouser/skirt size and non-occupational physical activity were not associated with IGFBP methylation in CRC. There were no clear associations between any of the energy balance-related exposures and specific tumor instability types based on MSI, CIMP and CIN.

Conclusions: This is the first study to show that methylation of IGFBP genes may be an important mechanism linking energy balance-related factors to colorectal cancer risk. Specific tumor instability types were less important.

Citation Format: Colinda C.J.M. Simons, Piet A. van den Brandt, R. Alexandra Goldbohm, Coen D.A. Stehouwer, Manon van Engeland, Matty P. Weijenberg. Molecular links between energy balance and colorectal cancer risk: A key role for methylation of insulin-like growth factor binding protein genes. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 38.