• Integrating Cell-Free DNA and Microbiome Signatures for Early Detection of Colorectal Cancer
  • Zahra Dahaghin,1,*
    1. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran


  • Introduction: Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, and its prognosis strongly depends on early detection. Current gold-standard diagnostic tools such as colonoscopy are accurate but invasive and often poorly accepted by patients. Liquid biopsy approaches analyzing cell-free DNA (cfDNA) have emerged as promising non-invasive alternatives, capturing tumor-derived mutations, methylation changes, and fragmentomic patterns. At the same time, research on the human microbiome has demonstrated that specific bacterial taxa, including Fusobacterium nucleatum and Bacteroides fragilis, are consistently associated with CRC. Recent findings indicate that fragments of microbial DNA can also be detected in plasma, suggesting that a combined cfDNA–microbiome approach could enhance early CRC detection.
  • Methods: A narrative review approach was applied. Relevant literature published between 2015 and 2024 was identified through searches in PubMed and Web of Science using the terms “cell-free DNA,” “colorectal cancer,” “liquid biopsy,” and “microbiome.” Articles were considered if they reported findings on cfDNA biomarkers, microbiome-related signatures, or studies proposing integration of these modalities. The selected publications were examined and summarized with a focus on diagnostic value, biological rationale, and methodological challenges.
  • Results: Analysis of published studies revealed that cfDNA methylation markers and fragmentomic features can detect CRC with high sensitivity, even in asymptomatic individuals. Microbiome studies consistently showed enrichment of tumor-associated bacteria such as Fusobacterium nucleatum in both stool and patient plasma. Importantly, microbial cfDNA has been identified in circulation, reflecting tumor associated dysbiosis. Early multi-omics investigations indicate that combining host cfDNA with microbial DNA increases diagnostic accuracy compared to single-modality approaches. These findings support the feasibility of dual biomarker strategies for non-invasive CRC detection.
  • Conclusion: The integration of cfDNA and microbiome-derived cfDNA represents a novel and promising pathway for early, non-invasive detection of colorectal cancer. This approach leverages complementary biological information: tumor genomic alterations and microbial community shifts. To translate this strategy into clinical practice, prospective validation in large cohorts, standardization of analytic pipelines, and cost-effectiveness assessments are essential.
  • Keywords: cell-free DNA; microbiome; colorectal cancer; liquid biopsy; early detection