AS584 - Epigenetic age as a marker of reproductive age and modifier of cancer risk among postmenopausal women

Investigator Names and Contact Information

Alexandra Binder (abinder@ucla.edu)

Introduction/Intent

Epigenetic age is a predictor of total cancer risk and mortality. An indicator of biological aging, epigenetic age is suggested to capture the influence of lifestyle and environmental exposures across the life course on cellular function. Among postmenopausal women, many predictors of cancer incidence are related to reproductive history. A few of the factors associated with an increased hazard of breast, endometrial and ovarian cancer in postmenopausal women have demonstrated to decelerate epigenetic aging. This is in contrast to prior studies of lung and total cancer incidence, which suggest that accelerated epigenetic aging is associated with increased cancer risk and mortality. We hypothesize there is a clinically relevant interaction between epigenetic age and the process of reproductive aging on hormonally responsive cancer risk among postmenopausal women. We propose analyzing epigenetic age within approximately 5,000 postmenopausal women from the Women’s Health Initiative (WHI) Observational Study and the control arm of the Clinical Trial with previously measured genome-wide methylation data (Ancillary Studies: AS311, AS315, BA23). This will include a subset of 1,382 women with bioavailable estradiol measurements, and 285 cases of invasive breast cancer. Epigenetic age acceleration (AgeAccel; deviance between chronological and epigenetic age) will be estimated in whole blood. We plan to (1) characterize the variation in AgeAccel associated with reproductive history, (2) assess how AgeAccel is influenced by lifestyle factors, (3) analyze the association between AgeAccel and bioavailable estradiol and testosterone, (4) investigate how these hormones may mediate and interact with modifiable and unmodifiable predictors of cancer risk to impact AgeAccel, and (5) estimate the association between AgeAccel and breast cancer hazard. Together these aims will separate the influences on biological aging from chronological age relevant for cancers associated with reproductive history among postmenopausal women. Additionally, this work will appraise the utility of AgeAccel to track the change in risk profile over time.

Specific Aims

1. Characterize the variation in AgeAccel associated with reproductive history (e.g. age of menarche, age of first birth, and oral contraceptive use)
2. Assess how AgeAccel is influenced by modifiable lifestyle factors associated with hormonally responsive cancer risk among postmenopausal women
3. Analyze the association between AgeAccel and postmenopausal bioavailable estradiol
4. Investigate how endogenous hormone levels may mediate and interact with modifiable and unmodifiable predictors of postmenopausal cancer risk to influence AgeAccel
5. Estimate the impact of AgeAccel on the hazard of postmenopausal invasive breast cancer and evaluate its utility for improving risk prediction models