IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-41774-w.html
   My bibliography  Save this article

Multimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization

Author

Listed:
  • Fenglong Bie

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Shandong Provincial Hospital Affiliated to Shandong First Medical University)

  • Zhijie Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yulong Li

    (Genecast Biotechnology Co., Ltd.)

  • Wei Guo

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yuanyuan Hong

    (Genecast Biotechnology Co., Ltd.)

  • Tiancheng Han

    (Genecast Biotechnology Co., Ltd.)

  • Fang Lv

    (Genecast Biotechnology Co., Ltd.)

  • Shunli Yang

    (Genecast Biotechnology Co., Ltd.)

  • Suxing Li

    (Genecast Biotechnology Co., Ltd.)

  • Xi Li

    (Genecast Biotechnology Co., Ltd.)

  • Peiyao Nie

    (Genecast Biotechnology Co., Ltd.)

  • Shun Xu

    (The First Hospital of China Medical University)

  • Ruochuan Zang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Moyan Zhang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Peng Song

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Feiyue Feng

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Jianchun Duan

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Guangyu Bai

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yuan Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Qilin Huai

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bolun Zhou

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yu S. Huang

    (Genecast Biotechnology Co., Ltd.)

  • Weizhi Chen

    (Genecast Biotechnology Co., Ltd.)

  • Fengwei Tan

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Shugeng Gao

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

Abstract

Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection.

Suggested Citation

  • Fenglong Bie & Zhijie Wang & Yulong Li & Wei Guo & Yuanyuan Hong & Tiancheng Han & Fang Lv & Shunli Yang & Suxing Li & Xi Li & Peiyao Nie & Shun Xu & Ruochuan Zang & Moyan Zhang & Peng Song & Feiyue F, 2023. "Multimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41774-w
    DOI: 10.1038/s41467-023-41774-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-41774-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-41774-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Peter Peneder & Adrian M. Stütz & Didier Surdez & Manuela Krumbholz & Sabine Semper & Mathieu Chicard & Nathan C. Sheffield & Gaelle Pierron & Eve Lapouble & Marcus Tötzl & Bekir Ergüner & Daniele Bar, 2021. "Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Dimitrios Mathios & Jakob Sidenius Johansen & Stephen Cristiano & Jamie E. Medina & Jillian Phallen & Klaus R. Larsen & Daniel C. Bruhm & Noushin Niknafs & Leonardo Ferreira & Vilmos Adleff & Jia Yuee, 2021. "Detection and characterization of lung cancer using cell-free DNA fragmentomes," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Stephen Cristiano & Alessandro Leal & Jillian Phallen & Jacob Fiksel & Vilmos Adleff & Daniel C. Bruhm & Sarah Østrup Jensen & Jamie E. Medina & Carolyn Hruban & James R. White & Doreen N. Palsgrove &, 2019. "Genome-wide cell-free DNA fragmentation in patients with cancer," Nature, Nature, vol. 570(7761), pages 385-389, June.
    4. Christoph Lengauer & Kenneth W. Kinzler & Bert Vogelstein, 1998. "Genetic instabilities in human cancers," Nature, Nature, vol. 396(6712), pages 643-649, December.
    5. Ruoyan Li & Lin Di & Jie Li & Wenyi Fan & Yachen Liu & Wenjia Guo & Weiling Liu & Lu Liu & Qiong Li & Liping Chen & Yamei Chen & Chuanwang Miao & Hongjin Liu & Yuqian Wang & Yuling Ma & Deshu Xu & Don, 2021. "A body map of somatic mutagenesis in morphologically normal human tissues," Nature, Nature, vol. 597(7876), pages 398-403, September.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Jiaqi Liu & Lijun Dai & Qiang Wang & Chenghao Li & Zhichao Liu & Tongyang Gong & Hengyi Xu & Ziqi Jia & Wanyuan Sun & Xinyu Wang & Minyi Lu & Tongxuan Shang & Ning Zhao & Jiahui Cai & Zhigang Li & Hon, 2024. "Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Anna-Lisa Doebley & Minjeong Ko & Hanna Liao & A. Eden Cruikshank & Katheryn Santos & Caroline Kikawa & Joseph B. Hiatt & Robert D. Patton & Navonil De Sarkar & Katharine A. Collier & Anna C. H. Hoge , 2022. "A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Jonathan C. M. Wan & Dennis Stephens & Lingqi Luo & James R. White & Caitlin M. Stewart & Benoît Rousseau & Dana W. Y. Tsui & Luis A. Diaz, 2022. "Genome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Michaël Noë & Dimitrios Mathios & Akshaya V. Annapragada & Shashikant Koul & Zacharia H. Foda & Jamie E. Medina & Stephen Cristiano & Christopher Cherry & Daniel C. Bruhm & Noushin Niknafs & Vilmos Ad, 2024. "DNA methylation and gene expression as determinants of genome-wide cell-free DNA fragmentation," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Derek Wong & Maha Tageldein & Ping Luo & Erik Ensminger & Jeffrey Bruce & Leslie Oldfield & Haifan Gong & Nicholas William Fischer & Brianne Laverty & Vallijah Subasri & Scott Davidson & Reem Khan & A, 2024. "Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Mingyun Bae & Gyuhee Kim & Tae-Rim Lee & Jin Mo Ahn & Hyunwook Park & Sook Ryun Park & Ki Byung Song & Eunsung Jun & Dongryul Oh & Jeong-Won Lee & Young Sik Park & Ki-Won Song & Jeong-Sik Byeon & Bo H, 2023. "Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Kate E. Stanley & Tatjana Jatsenko & Stefania Tuveri & Dhanya Sudhakaran & Lore Lannoo & Kristel Calsteren & Marie Borre & Ilse Parijs & Leen Coillie & Kris Bogaert & Rodrigo Almeida Toledo & Liesbeth, 2024. "Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    7. Sergi Elizalde & Ashley M Laughney & Samuel F Bakhoum, 2018. "A Markov chain for numerical chromosomal instability in clonally expanding populations," PLOS Computational Biology, Public Library of Science, vol. 14(9), pages 1-28, September.
    8. Jun Wang & Jinyong Huang & Yunlong Hu & Qianwen Guo & Shasha Zhang & Jinglin Tian & Yanqin Niu & Ling Ji & Yuzhong Xu & Peijun Tang & Yaqin He & Yuna Wang & Shuya Zhang & Hao Yang & Kang Kang & Xinchu, 2024. "Terminal modifications independent cell-free RNA sequencing enables sensitive early cancer detection and classification," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    9. van Wieringen Wessel N. & van de Wiel Mark A., 2014. "Penalized differential pathway analysis of integrative oncogenomics studies," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 13(2), pages 141-158, April.
    10. Dimitrios Mathios & Peter B. Bach & Jillian A. Phallen & Robert B. Scharpf & Victor E. Velculescu, 2022. "Reply to: Limitations of molecular testing in combination with computerized tomographic for lung cancer screening," Nature Communications, Nature, vol. 13(1), pages 1-2, December.
    11. Frederic W. Grannis, 2022. "Limitations of molecular testing in combination with computerized tomographic for lung cancer screening," Nature Communications, Nature, vol. 13(1), pages 1-2, December.
    12. Weissman, Daniel B. & Desai, Michael M. & Fisher, Daniel S. & Feldman, Marcus W., 2009. "The rate at which asexual populations cross fitness valleys," Theoretical Population Biology, Elsevier, vol. 75(4), pages 286-300.
    13. Paul R. Rosenbaum, 2004. "The Case-Only Odds Ratio as a Causal Parameter," Biometrics, The International Biometric Society, vol. 60(1), pages 233-240, March.
    14. Rui Zhao & Franziska Michor, 2013. "Patterns of Proliferative Activity in the Colonic Crypt Determine Crypt Stability and Rates of Somatic Evolution," PLOS Computational Biology, Public Library of Science, vol. 9(6), pages 1-15, June.
    15. Zimo Yang & Tao Zhou & Pak Ming Hui & Jian-Hong Ke, 2012. "Instability in Evolutionary Games," PLOS ONE, Public Library of Science, vol. 7(11), pages 1-9, November.
    16. Beibei Ru & Jinlin Huang & Yu Zhang & Kenneth Aldape & Peng Jiang, 2023. "Estimation of cell lineages in tumors from spatial transcriptomics data," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    17. Yoon Hee Cho & Su Young Kim & Hae Dong Woo & Yang Jee Kim & Sung Whan Ha & Hai Won Chung, 2015. "Delayed Numerical Chromosome Aberrations in Human Fibroblasts by Low Dose of Radiation," IJERPH, MDPI, vol. 12(12), pages 1-11, December.
    18. Rong Xiao & Deshu Xu & Meili Zhang & Zhanghua Chen & Li Cheng & Songjie Du & Mingfei Lu & Tonghai Zhou & Ruoyan Li & Fan Bai & Yue Huang, 2024. "Aneuploid embryonic stem cells drive teratoma metastasis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    19. Minghao Li & Zicheng Zhang & Qianrong Wang & Yan Yi & Baosheng Li, 2022. "Integrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    20. Yunyun An & Xin Zhao & Ziteng Zhang & Zhaohua Xia & Mengqi Yang & Li Ma & Yu Zhao & Gang Xu & Shunda Du & Xiang’an Wu & Shuowen Zhang & Xin Hong & Xin Jin & Kun Sun, 2023. "DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41774-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.