Body Size, Physical Activity, Early-Life Energy Restriction, and Associations with Methylated Insulin-like Growth Factor-Binding Protein Genes in Colorectal Cancer

Background: We investigated body size, physical activity, and early-life energy restriction in relation to colorectal tumors with and without methylated insulin-like growth factor-binding protein (IGFBP) genes, which are putative tumor-suppressor genes. Methods: We determined IGFBP2, IGFBP3, and IGFBP7 promoter CpG island hypermethylation in tumors of 733 colorectal cancer cases from the Netherlands Cohort Study (N = 120,852). Participants self-reported lifestyle and dietary factors at baseline in 1986. Using a case-cohort approach (N subcohort = 5,000), we estimated hazard ratios (HR) for colorectal cancer by extent of IGFBP methylation. Results: Comparison of the highest versus lowest sex-specific tertiles of adult body mass index (BMI) gave multivariable-adjusted HRs [95% confidence intervals (CI)] for colorectal cancers with 0 (18.7%), 1 (29.5%), 2 (32.4%), and 3 (19.5%) methylated genes of 1.39 (0.88-2.19), 1.11 (0.77-1.62), 1.67 (1.17-2.38), and 2.07 (1.29-3.33), respectively. Other anthropometric measures and physical activity were not associated with colorectal cancer risk by extent of IGFBP methylation, except height in sex-specific analyses for women. Exposure to energy restriction during the Dutch Hunger Winter versus nonexposure gave HRs (95% CIs) for colorectal cancers with 0, 1, 2, and 3 methylated genes of 1.01 (0.67-1.53), 1.03 (0.74-1.44), 0.72 (0.52-0.99), and 0.50 (0.32-0.78), respectively. Conclusions: Adult BMI, height (in women only), and early-life energy restriction were associated with the risk of having a colorectal tumor characterized by IGFBP methylation. Impact: Body size may particularly increase the risk of IGFBP gene-methylated colorectal tumors; this finding might facilitate more targeted approaches to prevent obesity-related colorectal cancers.