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

Abstract

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 ¼ 120,852). Participants self-reported lifestyle and dietary factors at baseline in 1986. Using a case-cohort approach (N subcohort ¼ 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. Cancer Epidemiol Biomarkers Prev; 23(9); 1852-62. Ó2014 AACR.

Cancer incidence in Holocaust male survivors—An Israeli cohort study

“…The researchers concluded that in those mostly exposed to hunger during the winter of 1944–1945 in the Netherlands compared with those least exposed, hyper‐methylation in IGFBP genes was associated with a significantly lower risk for colorectal cancer (HR = 0.72, 95%CI 0.52–0.99) (adjusting for BMI at age 20, adult BMI, change in BMI, size of clothes, height, and physical activity). In other words, those mostly exposed who also showed evidence of epigenetic changes that may have been caused by the exposure, were at a lower risk for colorectal cancer . These findings were in accordance with results of two age‐period‐cohort modeling studies, one from Norway, the other from other Nordic countries and Estonia .…”

“…Recently gene hyper‐methylation analyses are used to trace epigenetic changes that may mediate associations between early‐life exposure to energy restriction and colorectal cancer . A newly published analysis based on “The Netherlands Cohort Study” reported on colorectal cancer risk by hyper‐methylation of certain genes and by exposure to the Dutch hunger, adjusted for body size. The researchers concluded that in those mostly exposed to hunger during the winter of 1944–1945 in the Netherlands compared with those least exposed, hyper‐methylation in IGFBP genes was associated with a significantly lower risk for colorectal cancer (HR = 0.72, 95%CI 0.52–0.99) (adjusting for BMI at age 20, adult BMI, change in BMI, size of clothes, height, and physical activity).…”

Genetic variants and traits related to insulin-like growth factor-I and insulin resistance and their interaction with lifestyles on postmenopausal colorectal cancer risk

“…[19, 21, 22] Few studies have examined whether the association between obesity/obesity factors and CRC risk is affected by IGF-I/IR genetic variants. [17, 21, 23]; though the genetic variants have minimal or modest effect on the obesity–CRC relationship, it suggests that genetic variants related to IGF-I/IR traits and their signaling pathways interact with obesity and jointly influence CRC susceptibility.…”

Increased cancer incidence in Holocaust survivors and the implications for survivors of other extreme events

“…The same researchers also reported significantly increased plasma levels of insulin-like growth factor 1 (IGF-1) binding globulins in the exposed group, a finding that contradicted the expected shortterm response to starvation and that may explain the increased risk for breast cancer over time [23]. Interestingly, a more recent study that examined the relationship between body size, physical activity, early-life exposure to the 'hunger winter,' and associations with methylated IGF-1 binding protein (IGFBPs) genes in colorectal cancer, reported significantly inverse HRs in exposed (vs. non-exposed) subjects in the subgroups of 2 and 3 methylated IGFBP genes, implying that nutritional deprivation in early life may modify cancer risk in adulthood [24].…”