Abstract 7006: Identification of endothelial-cell-specific DNA methylation alterations in breast cancer with deconvolution of the tumor microenvironment

Abstract The tumor microenvironment (TME) plays a pivotal role in cancer progression, with tumor endothelial cells (TECs) emerging as key orchestrators of angiogenesis and vascular remodeling. Tumor-associated vasculature can have increased permeability and irregular blood flow, impacting drug delivery and tumor immune response. Understanding the molecular alterations within TECs may help identify targeted therapies and improve treatment outcomes with existing therapies. We combined TME cell-type deconvolution with modeling to identify cell-specific methylation alterations of TECs in breast cancer. Genome-scale DNA methylation array data accessed in GEO and GTEx from preinvasive, mixed, and invasive breast cancer tissue (n=609) & normal breast tissue (n=230). We applied HiTIMED, a reference-based cell-type deconvolution algorithm, to estimate endothelial and other cell-type proportions in the TME. Next, we applied CellDMC, a statistical algorithm that identifies cell-specific driven differential methylation, to our cell fraction results, unraveling differentially methylated positions occurring in the endothelial compartment of the angiogenic component of our breast tissue DNA methylation profiles. We identified 29 TEC driven differentially methylated positions (FDR ≤ 8e-03), including loci within genes in angiogenic pathways regulated by VEGF, endothelial inflammation and activation genes, and tumor-associated vasculature factors in the TME. Our findings suggest that variation in DNA methylation between TECs and normal endothelial cells is crucial to understanding the TME and providing insights into unknown cancer cell behaviors that contribute to tumor growth and metastasis, thus leading to the design of novel efficient therapies that target the malignant vascular component. Our study demonstrates the power of combining cell-type deconvolution and a modeling framework that identifies cell-specific somatic alterations to unravel the intricate characteristics of TECs in breast cancer. Furthermore, this study highlights the potential of DNA methylation profiling as a robust tool for characterizing TEC heterogeneity and elucidating the molecular basis of angiogenesis beyond breast tissue in the context of diverse cancer types. Our integrative approach holds promise for advancing precision oncology, paving the way for effective and targeted therapies aimed at modulating the tumor vasculature to impede cancer progression in breast cancer and other cancer types. Citation Format: Barbara Karakyriakou, Ze Zhang, Irma Vlasac, Pauline Mochama, Lucas Salas, Brock Christensen. Identification of endothelial-cell-specific DNA methylation alterations in breast cancer with deconvolution of the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7006.