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Colon
Original research
Early detection of colorectal cancer using aberrant circulating cell-free mitochondrial DNA fragmentomics
  1. Siyuan Wang1,
  2. Fan Peng1,
  3. Miao Dang1,
  4. Huanmin Jiao1,
  5. Huanqin Zhang1,
  6. Kaixiang Zhou1,
  7. Wenjie Guo1,
  8. Zhiyun Gong2,
  9. Lin Guo2,
  10. Renquan Lu2,
  11. Deliang Li3,
  12. Bingrong Liu3,
  13. Xu Guo1,
  14. Jinliang Xing1,
  15. Yang Liu4
  1. 1 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
  2. 2 Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
  3. 3 Department of Gatroenterology and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
  4. 4 Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
  1. Correspondence to Dr Yang Liu; liuyangfmmu{at}163.com; Professor Jinliang Xing; xingjl{at}fmmu.edu.cn

Abstract

Background Early detection of colorectal cancer (CRC) is crucial for improving the survival rates of patients.

Objective We aimed to develop a novel strategy for early CRC detection using the fragmentomic features of circulating cell-free mitochondrial DNA (ccf-mtDNA).

Design Here, a total of 1147 participants, including 478 healthy controls (HCs), 112 patients with advanced adenomas (AAs) and 557 patients with CRC, were enrolled from five hospitals and plasma samples were collected for capture-based ccf-mtDNA sequencing.

Results Our data analysis revealed significantly aberrant ccf-mtDNA fragmentomic features in patients with CRC and AA when compared with HCs. Then, a CRC detection (CD) model was constructed based on the fragmentomic features of ccf-mtDNA from 246 patients with CRC and 168 HC in the training cohort, showing area under the curve of 0.9863, sensitivity of 92.68% and specificity of 93.45%. Both internal and two external validation cohorts demonstrated the excellent capacity of CD model in distinguishing patients with early-stage CRC from HCs, greatly surpassing the performance of serum biomarkers. Furthermore, our CD model can also detect patients with AA with a sensitivity of 79.35% in AA cohort 1 and 85.00% in AA cohort 2.

Conclusion In conclusion, based on aberrant ccf-mtDNA fragmentomic features, a novel and non-invasive approach was established for the detection of patients with early-stage CRC or AA, with high performance.

  • COLORECTAL CANCER
  • CANCER GENETICS

Data availability statement

Data are available upon reasonable request. The raw sequencing data underlying this article are available in BIG Data Center, Beijing Institute of Genomics (BIG) with access number PRJCA028508.

https://doi.org/10.1136/gutjnl-2024-333533

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    Data availability statement

    Data are available upon reasonable request. The raw sequencing data underlying this article are available in BIG Data Center, Beijing Institute of Genomics (BIG) with access number PRJCA028508.

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    Footnotes

    • SW, FP and MD contributed equally.

    • Contributors YL and JX conceived and designed the project. SW, FP, MD, HZ, KZ, WG, ZG, LG, RL, DL, BL, XG and YL performed selection of patients, collection of samples, and clinical data and mtDNA sequencing. SW, FP, MD, HJ and YL analysed the sequencing data. SW, FP, MD, JX and YL prepared the manuscript. All coauthors reviewed and approved the final draft of the manuscript. YL and JX are the guarantors.

    • Funding This work was supported by the National Natural Science Foundation of China (grant nos. 82330073 and 82402731), the Science & Technology Co-ordination and Innovation Project of Shaanxi Province, China (grant no. 2023-ZDLSF-46), the clinical research program of Air Force Medical University (grant no. 2023LC2324).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.