Gene Expression and Epigenetic Landscapes of ecDNA in Cancer

Extrachromosomal DNA (ecDNA) is a novel topic in cancer biology due to its unique structural and functional roles in enhancing the oncogenic amplification and tumor heterogeneity. Unlike linear chromosomal DNA, ecDNA exists as circular DNA elements that frequently harbor oncogenes and regulatory sequences, contributing to aggressive tumor behavior, drug resistance, and poor clinical outcomes. This chapter examines the interplay between ecDNA and gene expression in cancer, highlighting how the epigenetic landscape—encompassing DNA methylation, histone modifications, and chromatin accessibility—facilitates transcriptional reprogramming. In this chapter, we delve into how the topological freedom of ecDNA allows for enhancer hijacking, high transcriptional output, and spatial clustering within the nucleus, forming “ecDNA hubs” that further potentiate oncogene expression. Recent advances in high-throughput sequencing, epigenomic profiling, and imaging techniques have uncovered the dynamic nature of ecDNA and its epigenetic modifications. We discuss emerging tools like ATAC-seq, ChIP-seq, and CRISPR screens that are being used to dissect ecDNA function. In addition, the chapter evaluates how ecDNA contributes to treatment resistance and the potential for targeting ecDNA-mediated mechanisms as a novel therapeutic strategy. Gaining insight into the epigenetic control of ecDNA presents a viable path for the development of precision oncology techniques.