Associations between Blood DNA Methylation and Estrogen Metabolism
Principal Investigator
Name
Gretchen Gierach
Degrees
Ph.D., M.P.H.
Institution
ITEB
Position Title
Deputy Chief and Senior Investigator
Email
About this CDAS Project
Study
PLCO
(Learn more about this study)
Project ID
PLCO-483
Initial CDAS Request Approval
May 28, 2019
Title
Associations between Blood DNA Methylation and Estrogen Metabolism
Summary
Estrogen is one of the main sex steroid hormones implicated in the development of hormonally-related cancers, including breast cancer. A previous analysis in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial and a follow-up meta-analysis found that the ratio of the 2-hydroxylation pathway to parent estrogens was statistically significantly associated with a decreased risk of postmenopausal breast cancer, after accounting for total estrogen levels. It is thought that both mitogenic and mutagenic mechanisms are important in estrogen-mediated carcinogenesis, but very little is known about the relationship between estrogens, including the different estrogen metabolites, and DNA methylation.
DNA methylation is a reversible epigenetic process of gene regulation which is thought to be important during carcinogenesis. Some studies have found that life style factors are associated with changes in DNA methylation, and there is some evidence to suggest that the metabolic control of the folate and methyl groups may be hormonally regulated. Methylation was recently measured in a subset of postmenopausal women in the PLCO trial using the EPIC methylation array. In the proposed project, we aim to investigate the relationship between methylation levels at individual sites interrogated by the EPIC methylation array and the different estrogen metabolites and their related metabolic pathways.
Another goal of this proposal is to study the relationship between DNA methylation clocks and estrogen metabolism. Aging is strongly correlated with changes in DNA methylation, and several so called “DNA methylation clocks” have been proposed to better account for the aging process. DNA methylation changes reflected through the biological clocks have been found to contribute to disease risk and mortality.
Lastly, DNA methylation is thought to impact genomic stability. We will therefore explore the relationship between genomic instability and estrogen metabolism pathways. These results could be informative as both an increased and decreased risk of breast cancer resulting from certain estrogen metabolic pathways could be related to the different levels of genomic instability. Genomic instability will be computed by means of DNA methylation as well as other biomarkers available in the PLCO trial.
DNA methylation is a reversible epigenetic process of gene regulation which is thought to be important during carcinogenesis. Some studies have found that life style factors are associated with changes in DNA methylation, and there is some evidence to suggest that the metabolic control of the folate and methyl groups may be hormonally regulated. Methylation was recently measured in a subset of postmenopausal women in the PLCO trial using the EPIC methylation array. In the proposed project, we aim to investigate the relationship between methylation levels at individual sites interrogated by the EPIC methylation array and the different estrogen metabolites and their related metabolic pathways.
Another goal of this proposal is to study the relationship between DNA methylation clocks and estrogen metabolism. Aging is strongly correlated with changes in DNA methylation, and several so called “DNA methylation clocks” have been proposed to better account for the aging process. DNA methylation changes reflected through the biological clocks have been found to contribute to disease risk and mortality.
Lastly, DNA methylation is thought to impact genomic stability. We will therefore explore the relationship between genomic instability and estrogen metabolism pathways. These results could be informative as both an increased and decreased risk of breast cancer resulting from certain estrogen metabolic pathways could be related to the different levels of genomic instability. Genomic instability will be computed by means of DNA methylation as well as other biomarkers available in the PLCO trial.
Aims
1. Analyze the relationship between each of the CpG sites in the EPCI methylation array and each estrogen metabolite and pathways.
2. Analyze the relationship between DNA methylation clocks and the different estrogen metabolites and pathways.
3. Investigate measures of genomic instability in relation to each estrogen metabolite and pathway.
Collaborators
Dr. Clara Bodelon (NCI/DCEG - ITEB)
Emily Riseberg (NCI/DCEG - ITEB)