ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1630231
This article is part of the Research TopicNew Advancement in Tumor Microenvironment Remodeling and Cancer Therapy, Volume IIView all 4 articles
Comprehensive fragmentation of cell-free repetitive DNA for enhanced cancer detection in plasma
Provisionally accepted
- 1Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- 2Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
- 3Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Beijing, China
- 4College of Bioinformatics Science and Technology, Harbin Medical University,, Harbin, China
- 5Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Background: Repetitive elements account for a large proportion of the human genome and undergo alterations in early tumorigenesis. The exclusive fragmentation pattern of DNA-derived cell-free repetitive elements (cfRE) remains unclear.Methods: This study enrolled 32 healthy volunteers and 112 patients with five types of cancer. A novel repetitive fragmentomics approach was proposed to profile cfRE using low-pass whole genome sequencing. Five repetitive fragmentomic features were innovatively designed: fragment ratio, fragment length, fragment distribution, fragment complexity, and fragment expansion. A machine learning-based multimodal model was developed using these features.The multimodal model achieved high prediction performance for early tumor detection even at ultra-low sequencing depth (0.1X, AUC=0.9824). Alu and STR were identified as the primary cfRE after filtering low-efficiency subfamilies. Characterization of cfRE within tumor-specific regulatory regions demonstrated accurate tissue origin prediction (0.1X, accuracy=0.8286) and identified aberrantly transcribed tumor driver genes.This study reveals the abundance of repetitive DNA in plasma. The innovative fragmentomics approach provides a sensitive, robust, and cost-effective method for early tumor detection and localization.
Keywords: cell-free DNA, Repetitive element, Early tumor detection, ToO, low-pass WGS
Received: 17 May 2025; Accepted: 16 Jun 2025.
Copyright: © 2025 Zhang, Dong, Rao, Mei, Hu, Liu, Zhen and Tang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wang Zhen, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Jianqiang Tang, Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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