Grant Abstract: Exercise Effects in Men & Women on Colon DNA Methylation

Grant Number: 5R21CA209203-02
PI Name: McTiernan
Project Title: Exercise Effects in Men & Women on Colon DNA Methylation

Abstract: This supplementation will expand work in the parent R21, which are to: 1) test the effect of a 12-month exercise intervention on colon biopsy tissue levels of DNA methylation of 4 candidate genes related to colon cancer (CRC) risk (EVL, MGMT, p14, and ESR1); 2) test effect modification by dose of exercise, weight and fat mass change; 3) explore effect modification by sex, colorectal adenoma history, family history of CRC, intake of folate and B vitamins; and 4) examine correlations between baseline DNA methylation of the 4 candidate genes with colon crypt proliferation (Ki67) and apoptosis (bax/bcl2). The supplementary work will explore associations of vitamin D supplement use biomarkers of CRC risk and with exercise effect on CRC biomarkers.
High levels of physical activity and of serum vitamin D are associated with reduced risk of developing CRC. In randomized controlled trials (RCTs), both exercise and vitamin D affect colon tissue biomarkers of CRC risk, such as proliferation and apoptosis. Our own work suggests that inflammation may be a key intermediary between vitamin D and CRC development. Little is known, however, about the combined effects of exercise and vitamin D on CRC risk. Therefore, we propose to explore this using the unique resources of a completed 12-month exercise RCT. Colorectal biopsy samples were collected at baseline in 102 men and 100 women aged 40-75 years. Participants were randomized to moderate-to-vigorous intensity aerobic exercise (goal 360 minutes/week) intervention or control. Mean 12-month exercise in intervention participants was 370 min/wk in men and 295 min/wk in women. 12-month colorectal biopsies were obtained in 187 (93%). Half of the participants reported using vitamin D supplements, and detailed information on type, dose, formulation, and frequency of use was collected. Supplementation work will include the following for baseline and follow-up data: abstraction and coding of detailed dosing for vitamin D supplement use; measurement of serum vitamin D to inform dose estimation; gene expression assays for genes related to inflammation, vitamin D, and CRC risk; and statistical analyses and interpretation.
The Specific Aims of this supplemental grant are to: 1) measure associations of vitamin D supplement use and dose with DNA methylation of CRC related candidate genes; 2) test associations of vitamin D supplement use and dose with biomarkers measured in colon biopsy tissue in the parent RCT, namely, Ki67, bax/bcl2, and prostaglandins (PGE2 and PGF2?); 3) examine whether vitamin D supplement use and dose modifies the effect of the parent RCT exercise intervention on these biomarkers; and 4) test associations of vitamin D supplement use and dose with expression in colorectal biopsies in genes related to vitamin D, inflammation, and CRC risk: IL6, TNFa, IL1ß, IL17, IL10, IL2, E-cadherin, VDR, Cyp27b1, and Cyp24a1. The proposed research is highly novel, takes advantage of an existing resource, and will inform future RCTs testing the independent and combined effects of exercise and vitamin D supplementation on CRC biomarkers.


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