Research Article: Aerobic exercise and DNA methylation in postmenopausal women: An ancillary analysis of the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial

Date Published: June 28, 2018

Publisher: Public Library of Science

Author(s): Devon J. Boyne, Will D. King, Darren R. Brenner, John B. McIntyre, Kerry S. Courneya, Christine M. Friedenreich, Hiromu Suzuki.


Physical activity is associated with a lower risk of breast, colon, and endometrial cancer. Epigenetic mechanisms such as changes in DNA methylation may help to explain these protective effects. We assessed the impact of a one year aerobic exercise intervention on DNA methylation biomarkers believed to play a role in carcinogenesis. The Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial was a two-armed randomized controlled trial in 320 healthy, inactive, postmenopausal women with no history of cancer. In an ancillary analysis, frozen blood samples (n = 256) were reassessed for levels of DNA methylation within LINE-1 and Alu repeats as well as within the promoter regions of APC, BRCA1, RASSF1, and hTERT genes. Differences between the exercise and control arm at 12-months, after adjusting for baseline values, were estimated within an intent-to-treat and per-protocol analysis using linear regression. No significant differences in DNA methylation between the exercise and control arms were observed. In an exploratory analysis, we found that the prospective change in estimated VO2max was negatively associated with RASSF1 methylation in a dose-response manner (p-trend = 0.04). A year-long aerobic exercise intervention does not affect LINE-1, Alu, APC, BRCA1, RASSF1, or hTERT methylation in healthy, inactive, postmenopausal women. Changes in DNA methylation within these genomic regions may not mediate the association between physical activity and cancer in healthy postmenopausal women. Additional research is needed to validate our findings with RASSF1 methylation.

Partial Text

Regular physical activity has been shown to protect against a multitude of cancers in a wide variety of study populations and settings. It is well established that being more physically active lowers the risk of colorectal, breast, and endometrial cancer [1, 2]. Emerging evidence suggests that exercise plays an important etiologic role in the prevention of other types of cancer as well. A recent pooled analysis of 1.44 million individuals suggested that the protective effects of physical activity also extend to head and neck, esophageal, lung, kidney, blood, and bladder cancers independent of body mass index [3]. The burden of cancer attributable to physical inactivity is considerable. It was recently estimated that roughly 7% of colorectal and breast cancer cases worldwide were attributable to physical inactivity in 2013, representing a total healthcare cost of $5.2 billion for these two cancer sites alone [4].

The flow of participants through the study and the numbers available for analysis are summarized in Fig 1. The two randomized groups were balanced with respect to baseline covariates (Table 1). The women included in these analyses had a mean age of 61.1 years (range = 50.6–74.9), a BMI of 29.2 kg/m2 (range = 20.4–43.9), and VO2max of 26.7 ml/kg/min (range = 11.5–52.2). Most of these participants (91.8%) were Caucasian.

In this group of healthy, inactive, postmenopausal women, a year-long exercise intervention did not have a significant impact on levels of DNA methylation within LINE-1 and Alu repeats or within the promoter regions of APC, BRCA1, RASSF1, or hTERT. The current state of epidemiologic evidence pertaining to the epigenetic effects of physical activity is disparate and has been previously reviewed [10, 38–40]. Few candidate gene studies targeting APC, BRCA1, RASSF1, or hTERT have been conducted [40]. Our null findings with respect to APC, BRCA1, and RASSF1 are consistent with results from two previous cross-sectional candidate gene studies in healthy women [41, 42] and several epigenome-wide association studies [40]. These null results might suggest that DNA methylation within these genes is tightly regulated in healthy individuals and is resistant to environmental influence.

A year-long aerobic exercise intervention did not impact levels of DNA methylation within LINE-1 and Alu repeats or within the promotor regions of the APC, BRCA1, RASSF1, and hTERT genes in the white blood cells of healthy, inactive, postmenopausal women. An exploratory analysis suggested that changes in physical fitness may be negatively associated with changes in RASSF1. Future large-scale studies examining changes in physical activity over longer periods of time in diverse study populations are required to validate these findings.




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