Methylation-Based Biological Age and Breast Cancer Risk

Abstract

Background: Age is one of the strongest predictors of cancer, chronic disease, and mortality, but biological responses to aging differ among people. Epigenetic DNA modifications have been used to estimate "biological age," which may be a useful predictor of disease risk. We tested this hypothesis for breast cancer.

Methods: Using a case-cohort approach, we measured baseline blood DNA methylation of 2764 women enrolled in the Sister Study, 1566 of whom subsequently developed breast cancer after an average of 6 years. Using three previously established methylation-based "clocks" (Hannum, Horvath, and Levine), we defined biological age acceleration for each woman by comparing her estimated biological age with her chronological age. Hazard ratios and 95% confidence intervals for breast cancer risk were estimated using Cox regression models. All statistical tests were two-sided.

Results: Each of the three clocks showed that biological age acceleration was statistically significantly associated with increased risk of developing breast cancer (5-year age acceleration, Hannum's clock: hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.00 to 1.21, P = .04; Horvath's clock: HR = 1.08, 95% CI = 1.00 to 1.17, P = .04; Levine's clock: HR = 1.15, 95% CI = 1.07 to 1.23, P < .001). For Levine's clock, each 5-year acceleration in biological age corresponded with a 15% increase in breast cancer risk. Although biological age may accelerate with menopausal transition, age acceleration in premenopausal women independently predicted breast cancer. Case-only analysis suggested that, among women who develop breast cancer, increased age acceleration is associated with invasive cancer (odds ratio for invasive = 1.09, 95% CI = 0.98 to 1.22, P = .10).

Conclusions: DNA methylation-based measures of biological age may be important predictors of breast cancer risk.

Figure 1.

Association between chronological age and the three epigenetic clocks. Scatterplots and Pearson correlation coefficients for chronological age and DNA methylation (DNAm) age estimated by the Hannum (A), Horvath (B), and Levine clocks (C) among non-Hispanic white women in the Sister Study.

Figure 2.

Age acceleration correlations and distributions. Pearson correlation matrix of the epigenetic age acceleration metrics (A) and violin plots of the distributions (B). “Clocks” + blood cell composition (BCC) are age acceleration metrics adjusted for BCC.

Figure 3.

Adjusted hazard ratios (and 95% confidence intervals [CI]) for the epigenetic age acceleration metrics (per 5-year increase). Associations shown for all breast cancer risk (A) and stratified by ductal carcinoma in situ risk (B) and invasive breast cancer risk (C). “Clocks” + blood cell composition (BCC) are age acceleration metrics adjusted for BCC.

Figure 4.

Adjusted hazard ratios (and 95% confidence intervals [CI]) for epigenetic age acceleration metrics (per 5-year increase) for invasive breast cancer risk. Associations stratified by menopausal status at diagnosis (A and B) and tumor estrogen receptor (ER) status (C and D). “Clocks” + blood cell composition (BCC) are age acceleration metrics adjusted for BCC.