Graduation Year

2025

Document Type

Thesis

Degree

M.S.

Degree Name

Master of Science (M.S.)

Degree Granting Department

Public Health

Major Professor

Xiaoming Liu, Ph.D.

Committee Member

Jacob Kresovich, Ph.D.

Committee Member

Dominic D'Agostino, Ph.D.

Committee Member

Kathleen Egan, Sc.D.

Keywords

Epigenetics, DNA Methylation, Immune Regulation, Cancer Survivorship, Biomarkers

Abstract

Breast cancer survivors face elevated risks of chronic inflammatory conditions and immunedysfunction compared to the general population. These elevated health risks in survivors are well-documented but mechanistically poorly understood. This study aimed to characterize longitudinal changes in DNA methylation patterns of immune-regulatory genes in women who developed breast cancer compared to cancer-free controls. We conducted an EWAS using Sister Study cohort data, analyzing longitudinal changes in DNA methylation by comparing the difference in beta values between pre- and post-diagnosis time points in breast cancer cases versus changes over the same period in cancer-free controls. The analysis included 414 participants: 189 women diagnosed with breast cancer between two blood draws and 225 cancer- free controls, with a mean interval of 7.7 years between the two blood collections. DNA methylation was measured in blood samples collected before and after breast cancer diagnosis and treatment. We focused on CpG sites associated with key immune-regulatory genes: TNF, IL- 6, IL-16, CCL2, CCL21 and CCL24. Four progressive statistical models were used: crude, age- adjusted, patient characteristics, and fully adjusted. We examined associations with and without adjustment for patient age (baseline and age difference), body mass index (baseline and age difference), race, treatment modalities (chemotherapy, radiation, endocrine therapy), and immune cell composition (CD4+ T cells, CD8+ T cells, monocytes, neutrophils, and NK cells). Significant differences in leukocyte composition emerged over time. The EWAS identified 1,647 CpG sites related to immune markers, with TNF, IL-6, and IL-16 genes prominently represented among the top findings across all models. Of these 1,647 immune-regulatory CpG sites, 95 to 100 sites showed nominally significant associations (p < 0.05) that warrant further investigation in larger studies. This study provides suggestive but statistically non-significant evidence for distinct DNA methylation patterns that warrant validation in larger studies. Consistent methylation signatures across models suggest coordinated epigenetic reprogramming following cancer treatment. While results did not reach statistical significance after multiple testing correction, the biological coherence and consistency of findings warrant validation in larger, independent cohorts. Future research should investigate whether these methylation signatures predict long-term health outcomes and could inform personalized survivorship care strategies.

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