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Non-invasive cancer screening; Early detection via liquid biopsy; Epigenetic signatures in gastrointestinal cancers; DNA methylation-based diagnostics; Blood-based colorectal cancer tests; Esophageal cancer methylation markers; Cell-free DNA analysis; Tumor-specific DNA methylation; cfDNA epigenomics in cancer; Circulating biomarkers for cancer screening; Minimal residual disease detection; Precision oncology biomarkers

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer globally and the second leading cause of cancer-related death. Esophageal cancer (EC), though less prevalent, is one of the deadliest malignancies due to its typically late diagnosis and aggressive nature [1]. Early detection is critical for improving survival rates in both cancers, as early-stage tumors are more amenable to curative interventions [2]. Traditional screening techniques, such as colonoscopy for CRC and endoscopy for EC, are effective but suffer from low compliance due to their invasive nature, preparation requirements, and cost. Stool-based DNA tests and serum tumor markers offer some utility but lack the sensitivity and specificity required for robust early detection [3].

In recent years, the field of liquid biopsy has emerged as a game-changer in oncology. Liquid biopsy refers to the analysis of tumor-derived material in bodily fluids—most notably, circulating tumor DNA (ctDNA) found in blood plasma [4]. Unlike traditional biopsies, this method is minimally invasive, repeatable, and reflective of real-time tumor dynamics. One of the most promising aspects of ctDNA analysis is the detection of aberrant DNA methylation patterns, which are among the earliest and most consistent epigenetic changes in tumorigenesis [4]. In response to these limitations, liquid biopsy has emerged as a promising non-invasive diagnostic alternative. This method leverages blood-based analysis of circulating tumor DNA (ctDNA)—small fragments of DNA shed into the bloodstream by cancer cells [5]. Among the most informative features of ctDNA are DNA methylation signatures, which represent early and widespread epigenetic changes that occur during tumor development. These methylation patterns are tissue-specific, stable, and detectable in minute concentrations, making them powerful biomarkers for cancer detection even in asymptomatic individuals [5].

Technological advancements in next-generation sequencing (NGS), digital PCR, and methylation enrichment techniques have significantly improved our ability to detect and interpret these epigenetic signals [6]. Unlike mutation-based approaches, methylation assays can target multiple cancer types simultaneously, improving the feasibility of multicancer early detection (MCED) efforts [7]. In the context of EC and CRC, where screening compliance and early detection remain major challenges, ctDNA methylation profiling offers a path toward personalized, minimally invasive, and widely accessible cancer diagnostics [8].

This article focuses on how ctDNA methylation profiling can facilitate the early detection of esophageal and colorectal cancers and reshape screening and surveillance paradigms.

Biology of ctDNA and DNA methylation

ctDNA refers to small fragments of DNA shed into the bloodstream by apoptotic or necrotic tumor cells. These fragments typically range from 150–200 base pairs and are intermixed with normal cell-free DNA (cfDNA) derived from healthy tissues. ctDNA carries tumor-specific alterations, including point mutations, copy number variations, structural rearrangements, and epigenetic modifications. Although ctDNA comprises a small fraction of total cfDNA—especially in early-stage cancers—its analysis has become increasingly feasible due to advances in ultra-sensitive sequencing technologies. DNA methylation involves the addition of methyl groups to cytosine residues, typically at CpG dinucleotides. Aberrant methylation, particularly promoter hypermethylation of tumor suppressor genes, is an early event in many cancers. Importantly, methylation changes are often tumor-type specific and more frequent than point mutations in early disease stages, making them excellent biomarkers for cancer detection.

Several methylation biomarkers have been validated for EC and CRC:

The methylated SEPT9 gene is the basis of an FDA-approved blood test (Epi proColon) for CRC screening [9].

Found to be hypermethylated in early CRC and adenomas. Promoter methylation of these genes is associated with colorectal neoplasia. Combined panels of these markers offer improved sensitivity and specificity for detecting early-stage CRC and advanced adenomas. Hypermethylation of these genes has shown potential in detecting esophageal squamous cell carcinoma (ESCC). These markers are involved in early carcinogenic processes and are detectable in ctDNA from EC patients. They are epigenetically silenced in esophageal adenocarcinoma (EAC). Integrating methylation markers from both adenocarcinoma and squamous subtypes may enhance detection across diverse patient populations [10].

Conclusion

Liquid biopsy based on ctDNA methylation signatures holds transformative potential for the early detection of esophageal and colorectal cancers. These epigenetic biomarkers are not only highly specific and stable but also detectable in minute quantities of plasma, making them ideal candidates for non-invasive screening strategies. As technology matures and clinical validation expands, ctDNA methylation profiling is poised to become a standard tool in precision oncology, enabling earlier intervention, better prognosis, and reduced mortality in gastrointestinal cancers. To fully realize this potential, efforts must be made to overcome technical and regulatory barriers, ensure equitable access, and integrate these tests into existing healthcare systems. With interdisciplinary collaboration and patient-centered innovation, methylation-based liquid biopsy will play a central role in the next generation of cancer diagnostics [11].