Author ORCID Identifier
0000-0002-1037-2698
Date of Award
Spring 5-8-2026
Document Type
Thesis (Ph.D.)
Department or Program
Cancer Biology
First Advisor
Brock Christensen
Abstract
Tumor epigenomes reflect a composite of malignant and non-malignant cellular signals, complicating interpretation of bulk DNA methylation data in heterogeneous tissues. In gynecologic cancers, where tumor progression, chromosomal instability, and microenvironmental variation are pronounced, failure to account for cellular composition obscures tumor-intrinsic regulatory remodeling and limits biomarker development. This dissertation advances a cell-type-aware epigenomic framework to disentangle specific DNA methylation alterations from compositional confounding and to extend methylation-based analysis to noninvasive biospecimens.
Using hierarchical reference-based deconvolution frameworks applied to large cohorts, cell-type-adjusted epigenome-wide analyses in endometrioid endometrial adenocarcinoma revealed coordinated epithelial-specific methylation remodeling associated with progression from early- to late-stage disease, enriched at regulatory elements and concordant with transcriptional reprogramming. In high-grade serous ovarian carcinoma, integration of structural genomic variation within diverse populations identified ancestry-associated differences and their potential contribution to tumor heterogeneity and disparities. Extending these methods beyond tumor tissue, DNA methylation-based cell typing of menstrual effluent demonstrated reproducible estimation of immune, epithelial, and stromal compartments across collection methods, supporting the feasibility of noninvasive epigenomic profiling for women’s health research.
Collectively, this work demonstrates that resolving cellular heterogeneity transforms bulk DNA methylation from a confounded composite signal into a scalable framework for interrogating tumor progression, structural genomic instability, and ancestry-associated variation. By integrating cell-type-resolved epigenomics across invasive and noninvasive contexts, this dissertation advances precision epigenomic approaches for gynecologic oncology and lays groundwork for equitable, noninvasive, population-scale biomarker development.
Original Citation
Vlasac, I. M., Stolrow, H. G., Thayer, Z. M., Christensen, B. C., & Rivera, L. (2025). DNA-based cell typing in menstrual effluent identifies cell type variation by sample collection method: toward noninvasive biomarker development for women’s health. Epigenetics, 20(1). https://doi.org/10.1080/15592294.2025.2453275
Recommended Citation
Vlasac, Irma, "Precision Epigenomics in Gynecologic Disease: Cell-Type-Resolved DNA Methylation Analysis from Tumor Tissue to Noninvasive Biospecimens" (2026). Dartmouth College Ph.D Dissertations. 484.
https://digitalcommons.dartmouth.edu/dissertations/484
Genomic enrichment feature segment tests versus reference
2_Supplementary_Table_epithelial_genomic_enrichment_feature_segment_tests_vs_reference.csv (5 kB)
Epithelial-specific genomic enrichment feature segment tests versus reference
3_Supplementary_Table_promoter_both_genexp_DNAm_tbl.csv (6 kB)
Promoter-associated genes with concordant differential expression and DNA methylation
4_Supplementary_Table_enhancer_both_geneexpression_DNAm_tbl.csv (3 kB)
Enhancer-associated genes with concordant differential expression and DNA methylation
5_Supplementary_Table_GSEA_Advanced_vs_Early_cellAdj.csv (122 kB)
GSEA results: Late-stage versus Early-stage (cell-type adjusted model)
6_Supplementary_Table_epithelial_promoter_enhancer_comb_expression_and_DNAm.csv (161 kB)
Epithelial promoter and enhancer combined gene expression and DNA methylation results
7_Supplementary_Table_GSEA_Hallmark_Reactome_EpiInteraction_results.xlsx (40 kB)
GSEA Hallmark and Reactome epithelial interaction pathway results
