"Extrachromosomal circular DNA (eccDNA): A key driver of tumorigenesis, drug resistance, and prognosis across gastrointestinal malignancies”

Extrachromosomal circular DNA (eccDNA) are independent DNA fragments found in mammalian cells, playing a crucial role in oncogene amplification and tumor progression. These circular DNA molecules promote genetic diversity and plasticity, contributing to cancer evolution and drug resistance. Their presence in circulation as cell-free DNA makes them promising biomarkers for cancer diagnosis and monitoring treatment responses. While implicated in various malignancies, this review spotlights their pivotal role in gastrointestinal malignancies. In hepatocellular carcinoma (HCC), over 230,000 eccDNAs have been identified, many correlating with changes in gene expression and tumor aggressiveness. These molecules frequently harbor genes involved in key oncogenic pathways including AKT, STAT3, MAPK, NOTCH, and WNT, while CK19-positive HCCs, often more aggressive, may be driven by eccDNA-associated genomic instability. Similarly, in hypopharyngeal squamous cell carcinoma (HSCC), eccDNA-mediated gene amplifications contribute to resistance against chemotherapeutic agents like methotrexate and cisplatin. In gastric cancer, eccDNAs amplify critical oncogenes such as ERBB2, CCNE1, and MYC, influencing tumor progression. Colorectal cancer also exhibits eccDNA-driven resistance, particularly through amplification of the DHFR gene. In esophageal squamous cell carcinoma (ESCC), differentially expressed eccDNAs are linked to the modulation of regulatory elements and oncogenic signaling pathways such as MAPK. Furthermore, eccDNAs in perihilar cholangiocarcinoma (pCCA) have emerged as robust prognostic markers, reflecting tumor behavior and treatment response. Collectively, the evidence underscores eccDNA’s multifaceted role in cancer, supporting their exploration as diagnostic tools and therapeutic targets. Ongoing research is critical to fully elucidate their mechanistic contributions and unlock their clinical utility across diverse malignancies.