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Effects of Aspirin, Hormone Replacement Therapy, Smoking, and BMI on Age- and Cancer-Associated DNA Methylation in the Colon in Women

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Key Points

  • Aspirin and hormone-replacement therapy use were associated with reduced age-related DNA methylation, and smoking and high BMI were associated with increased methylation.
  • These factors had similar effects on methylation of colorectal cancer–related genes.

In a study reported in the Journal of the National Cancer Institute, Noreen et al found that aspirin and hormone-replacement therapy reduced age-related gene promoter DNA methylation, and smoking and high body mass index (BMI) increased methylation in the colonic mucosa in women. Similar relationships were observed between these factors and methylation of colorectal cancer–related genes.

Age-Related Methylation

Of 20,025 promoter-associated CpGs—that is, sites where a cytosine nucleotide and a guanine nucleotide are separated by a single phosphate—analyzed in normal colon biopsies from 1,092 women in a screening cohort, 1,713 showed statistically significant age-dependent methylation. Methylation gains were found in fewer long-term (≥ 2 years) aspirin users (43 vs 1,355 in nonusers) and users of hormone-replacement therapy aged ≥ 50 years (1 vs 1,377 in nonusers) and in more smokers with ≥ 20-year smoking history (180 vs 39 in nonsmokers) and subjects with BMI ≥ 25 kg/m2 (554 vs 144 in those with normal BMI).

Changes in Cancer-Related Methylation

Of the CpGs exhibiting age-related methylation, 50% were found to be hypermethylated in colorectal cancer samples from 59 women (odds ratio [OR] = 20, P < 2 × 10-16); these CpGs gained methylation at a higher median rate compared with sites with only age-related methylation (P = 2 × 10-76) and were more likely to exhibit polycomb regions (OR = 3.67, P = 1 × 10-38).

Rates of methylation change at promoters of the established colorectal cancer–associated genes were significantly reduced in aspirin users (methylation rate ratio [MRR] = 0.53, P < .001) and in women using hormone-replacement therapy (MRR = 0.54, P < .001) compared with nonusers and significantly increased in smokers vs nonsmokers (MRR = 4.0, P < .001) and in women with high vs normal BMI (MRR = 1.57, P = .004).

The investigators concluded, “Lifestyle, including aspirin use, modulates age-associated DNA methylation change in the colonic epithelium and thereby impacts the evolution of cancer methylomes.”

Primo Schär, PhD, of University of Basel, is the corresponding author for the Journal of the National Cancer Institute article.

The study was supported by the Swiss Cancer League, Association for International Cancer Research, Stanley Thomas Johnson Foundation, and OPO Foundation.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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