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DNA remnants in red blood cells enable early detection of cancer

Cell Research volume 35, pages 568–587 (2025)Cite this article

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Abstract

Cytoplasmic DNA emerges as a consequence of genomic instability. However, its potential role in disease diagnosis has yet to be fully explored. Here we analyzed DNA remnants in mature red blood cells (rbcDNA) from both healthy individuals and cancer patients. Our study unveiled distinct genomic profiles in rbcDNA from cancer patients with early-stage solid tumors compared to those of healthy donors. Significant changes in read counts at specific genomic regions within rbcDNA were identified in patients, which were termed tumor-associated rbcDNA features. These features demonstrated potential for highly accurate early-stage cancer detection, proposing a novel approach for cancer detection. Moreover, tumor-associated rbcDNA features were observed in tumor mouse models, with some features being conserved between mice and humans. Chronic, but not transient, up-regulation of interleukin-18 is essential for the development of these features by promoting DNA damage in bone marrow hematopoietic cells through the up-regulation of NR4A1. These results underscore the remote regulation of chromosomal stability in hematopoietic cells by solid tumors and propose tumor-associated rbcDNA features as a promising strategy for early cancer detection.

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Fig. 1: Characterization of rbcDNA isolated from human RBCs.
Fig. 2: Distinct genomic profiles of rbcDNA from cancer patients.
Fig. 3: Tumor-associated rbcDNA signature enables early cancer detection.
Fig. 4: Preference of tumor-associated rbcDNA signature in cancer detection is independent of clinical characteristics.
Fig. 5: Induction of IL-18 during tumor progression is essential for the formation of tumor-associated rbcDNA signature.
Fig. 6: IL-18 signaling promotes DNA damage in BM hematopoietic cells from tumor-bearing mice.
Fig. 7: NR4A1 is essential for tumor-associated rbcDNA signature formation.

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Data availability

This study did not generate new unique materials. The data described in this manuscript have been deposited in the Genome Sequence Archive (GSA) in the national genomics data center. The assigned accession numbers of the submission are HRA006186 for the human datasets and CRA013839 for the mouse datasets. The supplemental materials can be found in Supplementary information, Tables S1–S18. All data are available in the main text or the supplementary materials.

All analyses were performed using previously published or developed tools, as indicated in Materials and Methods. The pipeline and software versions used for analysis and visualization are available on GitHub at https://github.com/GaoXlab/MNDNA_scripts_forSun.

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Acknowledgements

We appreciate the technical support from the Biomedical Research Core Facilities, Westlake High-Performance Computing Center, and Laboratory Animal Resources Center of Westlake University. We thank Dr. Jian Yang (Westlake University) for advice on data analysis, Dr. Hui Lin (Zhejiang University), Xiaoxiao Fan (Zhejiang University) and Xiaojie Huang (Zhejiang University) for advice on blood sample collection. Schematic figures were generated with BioRender (https://app.biorender.com/). This project was supported in part by grants from the National Natural Science Foundation of China (81973993), Zhejiang Provincial Natural Science Foundation of China (LR20C070001), Hangzhou Science and Technology Major Project (2018HZKJSA10095), and Key Research and Development Program of Zhejiang Province (2024C03170).

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Author notes

  1. These authors contributed equally: Haobo Sun, Xingyun Yao.

Authors and Affiliations

  1. School of Basic Medical Science, Fudan University, Shanghai, China

    Haobo Sun

  2. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China

    Haobo Sun, Xingyun Yao, Ying Li, Jianping Ge & Xiaofei Gao

  3. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China

    Haobo Sun, Xingyun Yao & Xiaofei Gao

  4. Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China

    Haobo Sun, Xingyun Yao & Xiaofei Gao

  5. College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China

    Xingyun Yao

  6. Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Yurong Jiao, Xiangxing Kong, Jun Li & Kefeng Ding

  7. Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Yuehua Han

  8. Department of Gastroenterology, Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China

    Yanfei Cao

  9. Department of Pathology, Taizhou Central Hospital Taizhou University Hospital, Taizhou, Zhejiang, China

    Hongsheng Lu

  10. Department of Respiratory Medicine, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China

    Pingli Wang

  11. Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Yu Xu

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H.S. and X.Y. contributed to methodology, investigation, visualization, project administration, original draft preparation, and manuscript review and editing. Y.J., X.K., Y.H., H.L., Y.C., and Y.X. participated in the investigation, including clinical sample collection and analysis. Y.L. and J.G. contributed to methodology. P.W., J.L., and K.D. provided supervision. X.G. conceptualized the study, contributed to methodology, investigation and visualization, acquired funding, administered the project, supervised the research, and contributed to original draft preparation, review, and editing. All authors discussed the results and provided comments on the manuscript.

Corresponding author

Correspondence to Xiaofei Gao.

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Competing interests

The authors declare the following financial or non-financial competing interest: X.G. is a shareholder of Timing Biotech Co., Ltd. The remaining authors declare no competing interests.

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Sun, H., Yao, X., Jiao, Y. et al. DNA remnants in red blood cells enable early detection of cancer. Cell Res 35, 568–587 (2025). https://doi.org/10.1038/s41422-025-01122-7

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