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Background <p>Delayed detection of recurrence significantly contributes to colorectal cancer (CRC) mortality, underscoring the need for robust prognostic biomarkers. Although extrachromosomal circular DNA (eccDNA) is a known oncogenic driver, its prognostic utility in CRC remains largely unexplored.</p> Methods <p>In this 6-year prospective cohort study, full-length eccDNA profiling of 153 plasma samples was performed using Nanopore sequencing. Differential eccDNA signatures between recurrence (R, <i>n</i> = 20) and non-recurrence (NR, <i>n</i> = 133) patients enabled construction of predictive models for recurrence and mortality. Functional validation of eccDNAs was conducted in HCT116 cells.</p> Results <p>Compared to NR patients, R patients exhibited enrichment of eccDNAs derived from chromosome 9, shorter median eccDNA lengths, and reduced variability in eccDNA length. All 4.9–5.0&#xa0;kb eccDNAs derived from <i>CKM</i>, while other eccDNAs showed a strong genomic distribution correlation between groups (Spearman’s ρ = 0.73). Promoter-derived eccDNAs were enriched in R patients, particularly from the promoter of <i>CARD9</i> (eccPromoter-CARD9, 10.4-fold increase). Overexpression of eccPromoter-CARD9 significantly promoted CRC cell proliferation and migration. R patients exhibited elevated eccDNAs harboring the hsa-mir-374c cluster in plasma and tissues, and their corresponding miRNAs demonstrated exceptional diagnostic accuracy in CRC-related TCGA cohorts. An eccDNA-based random forest classifier achieved superior recurrence prediction accuracy (AUC &gt; 0.8), correlating with shorter time-to-recurrence (HR = 3.79) and elevated CA125 and CEA levels. Additional eccDNA-based models effectively predicted recurrence-associated mortality (AUC ≥ 0.93).</p> Conclusions <p>The plasma eccDNA landscape may serve as an early and powerful non-invasive biomarker for CRC prognostication, optimizing risk stratification and guiding personalized treatment.</p>

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Circulating extrachromosomal circular DNA as a prognostic biomarker for colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Xuanmei Luo,
  • Jian Cui,
  • Jinxin Shi,
  • Gaoyuan Sun,
  • Lili Zhang,
  • Yayu Li,
  • Yingyu Guo,
  • Lu Kuai,
  • Tianhan Sun,
  • Qi Luo,
  • Jiahui Cai,
  • Qi An,
  • Wei Zhang,
  • Fei Xiao,
  • Gang Zhao

摘要

Background

Delayed detection of recurrence significantly contributes to colorectal cancer (CRC) mortality, underscoring the need for robust prognostic biomarkers. Although extrachromosomal circular DNA (eccDNA) is a known oncogenic driver, its prognostic utility in CRC remains largely unexplored.

Methods

In this 6-year prospective cohort study, full-length eccDNA profiling of 153 plasma samples was performed using Nanopore sequencing. Differential eccDNA signatures between recurrence (R, n = 20) and non-recurrence (NR, n = 133) patients enabled construction of predictive models for recurrence and mortality. Functional validation of eccDNAs was conducted in HCT116 cells.

Results

Compared to NR patients, R patients exhibited enrichment of eccDNAs derived from chromosome 9, shorter median eccDNA lengths, and reduced variability in eccDNA length. All 4.9–5.0 kb eccDNAs derived from CKM, while other eccDNAs showed a strong genomic distribution correlation between groups (Spearman’s ρ = 0.73). Promoter-derived eccDNAs were enriched in R patients, particularly from the promoter of CARD9 (eccPromoter-CARD9, 10.4-fold increase). Overexpression of eccPromoter-CARD9 significantly promoted CRC cell proliferation and migration. R patients exhibited elevated eccDNAs harboring the hsa-mir-374c cluster in plasma and tissues, and their corresponding miRNAs demonstrated exceptional diagnostic accuracy in CRC-related TCGA cohorts. An eccDNA-based random forest classifier achieved superior recurrence prediction accuracy (AUC > 0.8), correlating with shorter time-to-recurrence (HR = 3.79) and elevated CA125 and CEA levels. Additional eccDNA-based models effectively predicted recurrence-associated mortality (AUC ≥ 0.93).

Conclusions

The plasma eccDNA landscape may serve as an early and powerful non-invasive biomarker for CRC prognostication, optimizing risk stratification and guiding personalized treatment.