Transforming Cancer Diagnostics: The Emergence of Liquid Biopsy and Epigenetic Markers

Abstract

Liquid biopsy represents a transformative approach in oncology, enabling noninvasive disease detection and monitoring through epigenetic signals in circulating tumor DNA (ctDNA), nucleosomes, and noncoding RNAs. Tumor initiation is driven by epigenetic modifications, including DNA methylation, histone alterations, and dysregulated noncoding RNAs, which disrupt gene regulation, cell cycle control, DNA repair, and metastatic processes. This review systematically examines recent evidence on DNA methylation, histone marks (e.g., H3K27me3, H3K18ac), and noncoding RNAs (miRNAs, lncRNAs) as biomarkers for early cancer detection, prognosis, and therapeutic response. Particular focus is placed on aberrant DNA methylation (e.g., hypermethylation of CDKN2A, RASSF1A) and altered histone modifications (e.g., EZH2-mediated silencing) as indicators of tumor heterogeneity and evolution. Stable and specific in biofluids, noncoding RNAs such as oncogenic miR-21, tumor-suppressive miR-34a, and metastasis-associated MALAT1/HOTAIR further enhance clinical applicability. Recent detection methods, including bisulfite sequencing, ChIP-seq, and RNA-seq, have advanced biomarker profiling, though challenges remain in standardization and low-abundance detection. With over 12 active clinical studies validating their utility, integration of epigenetic markers with AI and multiomics holds promise for individualized, dynamically guided oncology care. Future innovations, such as chromatin accessibility analysis and cfDNA fragmentation profiling, may further refine diagnostic precision and therapeutic monitoring.

Keywords: DNA methylation; cancer diagnostics; epigenetic markers; liquid biopsy; noncoding RNAs.

FIGURE 1

Overview of the analytes examined and diagnostic information provided by liquid biopsy: This figure summarizes the key analytes detectable in liquid biopsy samples, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and microRNAs, along with the types of clinically actionable information they provide, such as molecular diagnoses, tumor heterogeneity, and marker‐guided personalized treatment (adapted from ref. [189]. https://doi.org/10.1186/s12943‐022‐01543‐7 by license CC BY 4.0 Copyright 2022 The Authors).

FIGURE 2

Mechanism of DNA methylation: this schematic summarizes key pathways involved in the establishment, maintenance, and removal of DNA methylation marks—including de novo methylation by DNMT3A/B, maintenance methylation by DNMT1, and active demethylation via TET enzymes and TDG‐mediated base excision repair—illustrating the dynamic regulation of epigenetic states in gene expression control (created with BioRender.com).

FIGURE 3

Histone modifications and chromatin remodeling involved in transcriptional reprogramming in cancer: This figure illustrates key epigenetic alterations—including histone acetylation, methylation, and chromatin remodeling—that contribute to dysregulated gene expression in cancer. These modified chromatin segments can be detected from blood (and other body fluids) by various techniques such as chromatin immunoprecipitation (ChIP), mass spectrometry, immunofluorescence assays, and Western blotting for diagnosis of cancer (created with BioRender.com).

FIGURE 4

Coordinated epigenetic mechanisms in cancer progression: chromatin remodeling, DNA methylation, and noncoding RNAs collectively disrupt gene expression programs to drive cellular transformation and tumor development, highlighting their roles in silencing tumor suppressors, activating oncogenes, and promoting malignant phenotypes (created with BioRender.com).