||1R03CA241956-01A1 Interpret this number
||Case Western Reserve University
||Breast Cancer Risk Factors and Epigenetic Age Acceleration
Cancer is the second leading cause of death in the United States, and breast cancer (BrCa) is the most
diagnosed malignancy among women, and the second highest cause of cancer deaths. Despite lower overall
incidence, African American (AA) women experience an earlier age of onset of BrCa and have significantly higher
mortality rates compared to white women diagnosed with BrCa. Although screening, access and treatment may
contribute to some of this disparity, it is clear that there are additional mechanisms underlying these disparities.
New research suggests that racial differences in epigenetic profiles may be crucial for explaining inequalities of
Epidemiological studies have identified numerous factors associated with risk of developing BrCa.
Hormonal factors, such as parity, age at first birth, age at menarche and oral contraceptive use, all have well
established associations with BrCa risk. A number of other factors are also associated with BrCa risk, including
body mass index (BMI), physical activity, family history, and specific genetic risk variants. However, additional
research is needed to determine the underlying biological pathways of these well-established risk factors with
BrCa risk. Interestingly, data in the literature suggests that effects of these risk factors differ by race, having
smaller or larger effects on BrCa risk in AA populations compared to white populations.
Epigenetic variants, including DNA methylation, are modifications to DNA that are both heritable and
variable based on environmental variation. Epigenetic mechanisms thus may represent a link between genetic
and environmental risk factors that underlie the development of BrCa, and also may explain racial differences in
effect of risk factors for breast cancer. Two independent groups have recently identified that DNA methylation
based on a handful of markers throughout the genome robustly predicts an individual’s chronological age and
thus captures the ‘epigenetic clock’ for biological aging. It has been shown that ‘epigenetic age acceleration’ –
the difference between methylation-predicted age and chronological age – is consistently associated with overall
mortality and many age-related diseases including cancer. It has been further shown that epigenetic aging rates
are significantly associated with race, sex, and with known cancer risk factors such as smoking and obesity,
providing the first human evidence suggesting aging-related epigenetic processes are potential molecular
underpinnings for racial health disparities.
In this project, we will conduct a pilot project that will examine the impact of epigenetic age on the effect
of known environmental and lifestyle risk factors for BrCa as it relates to breast cancer risk and then test to see
if they differ by race. We will measure epigenetic age through methylation profiling of breast tissue and blood to
evaluate (1) ability of blood epigenetic age to correlate with breast tissue epigenetic age; (2) assess differences
by race and (3) to provide preliminary data on the correlation of breast epigenetic age with breast cancer risk
This proposal will provide the important preliminary data to expand this line of inquiry understanding
environmental, genetic and epigenetic factors in BrCa carcinogenesis and BrCa disparities. The samples
included in this project are from a large BrCa case-control study, and includes a socioeconomic status and
racially diverse group of patients recruited from the Case CCC catchment area. This proposal will facilitate the
generation of necessary pilot data for a larger R01 level grant to more fully study this important line of inquiry.