Abstract P1-09-08: Hormonal factors associated with elevation of DNA methylation age in breast tissue of healthy women
Authors: Sehl ME , Henry JE , Storniolo AM , Horvath S , Ganz PA 
Published: May 2019

Abstract
Background: Healthy breast tissue appears older than matched peripheral blood, when using a biologic aging measurement based on DNA methylation markers. The underlying cause of this acceleration is not known. We hypothesize that cumulative estrogen exposure is associated with accelerated breast epigenetic aging. In this study, we examined factors associated with breast epigenetic age in a healthy population of women.
Methods: We used breast tissue samples from 232 healthy women donors (119 pre-menopausal, 113 post-menopausal) to the Komen Tissue Bank, with data available on variables related to cumulative estrogen exposure, including age at menarche, gravidity, parity, and menopausal status. DNA methylation experiments were performed using the Illumina EPIC 850K array platform. DNA methylation age (DNAm age) was calculated using the epigenetic clock methods developed by Horvath (2013). Total years of estrogen exposure was calculated as the difference between age at menopause (or current age) - number of live births x 9 months – number of miscarriages x 3 months. Nonparametric group testing was used to compare mean levels of the difference between DNAm age and chronologic age for pre- and post-menopausal groups. We examined the outcome “age acceleration”, calculated using the residuals of the regression of DNAm age versus chronologic age, because it is age-adjusted and independent of cell distribution. Multivariate linear regression models were used to examine for associations between age acceleration and each of our covariates.
Results: Our sample included women aged 19-90 years (mean age 50.7, SD 11.8), with 114 nulliparous women. We confirmed that DNAm age in breast tissue is strongly correlated with chronologic age (ρ=0.89, p&lt;0.0001). The difference between DNAm age and chronologic age is greater at earlier ages, and is significantly greater in premenopausal women (mean 8.9 years, SE 0.04), compared with postmenopausal women (mean 2.7 years, SE 0.05) (p&lt;0.0001). Age acceleration was significantly associated with earlier age at menarche (β=-0.395 for each year, p=0.036). For women with limited total years of exposure to estrogen (&lt;19 years), there was a significant association between age acceleration and total estrogen exposure and β=0.673 for each year, p=0.028).
Conclusion: Acceleration of epigenetic age in breast tissues occurs in healthy women and is most pronounced in the pre-menopausal period. Earlier age at menarche and total years of estrogen exposure are associated with higher degree of acceleration, suggesting that cumulative estrogen exposure drives this process.
Citation Format: Sehl ME, Henry JE, Storniolo AM, Horvath S, Ganz PA. Hormonal factors associated with elevation of DNA methylation age in breast tissue of healthy women [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-08.