IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-23445-w.html
   My bibliography  Save this article

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden

Author

Listed:
  • Peter Peneder

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Adrian M. Stütz

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Didier Surdez

    (INSERM U830, Équipe Labellisée LNCC, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre
    Balgrist University Hospital, University of Zurich)

  • Manuela Krumbholz

    (University Hospital Erlangen)

  • Sabine Semper

    (University Hospital Erlangen)

  • Mathieu Chicard

    (INSERM U830, Équipe Labellisée LNCC, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre)

  • Nathan C. Sheffield

    (Center for Public Health Genomics, University of Virginia)

  • Gaelle Pierron

    (Unité de Génétique Somatique, Service d’oncogénétique, Institut Curie, Centre Hospitalier)

  • Eve Lapouble

    (Unité de Génétique Somatique, Service d’oncogénétique, Institut Curie, Centre Hospitalier)

  • Marcus Tötzl

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Bekir Ergüner

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Daniele Barreca

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • André F. Rendeiro

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Abbas Agaimy

    (Institute of Pathology, University Hospital Erlangen)

  • Heidrun Boztug

    (St. Anna Kinderspital, Department of Pediatrics, Medical University)

  • Gernot Engstler

    (St. Anna Kinderspital, Department of Pediatrics, Medical University)

  • Michael Dworzak

    (St. Anna Kinderspital, Department of Pediatrics, Medical University)

  • Marie Bernkopf

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Sabine Taschner-Mandl

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Inge M. Ambros

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Ola Myklebost

    (Institute for Cancer Research, Oslo University Hospital
    University of Bergen)

  • Perrine Marec-Bérard

    (Pediatric Department, Hematology and Oncology Pediatric Institute, Centre Léon Bérard)

  • Susan Ann Burchill

    (Children’s Cancer Research Group, Leeds Institute of Medical Research, St. James’s University Hospital)

  • Bernadette Brennan

    (Royal Manchester Children’s Hospital)

  • Sandra J. Strauss

    (Department of Oncology, UCL Cancer Institute
    University College London Hospital)

  • Jeremy Whelan

    (University College London Hospital)

  • Gudrun Schleiermacher

    (INSERM U830, Équipe Labellisée LNCC, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre)

  • Christiane Schaefer

    (University Hospital Essen, Pediatrics III, West German Cancer Centre)

  • Uta Dirksen

    (University Hospital Essen, Pediatrics III, West German Cancer Centre)

  • Caroline Hutter

    (St. Anna Children’s Cancer Research Institute (CCRI)
    St. Anna Kinderspital, Department of Pediatrics, Medical University)

  • Kjetil Boye

    (Oslo University Hospital, The Norwegian Radium Hospital)

  • Peter F. Ambros

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Olivier Delattre

    (INSERM U830, Équipe Labellisée LNCC, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre
    Unité de Génétique Somatique, Service d’oncogénétique, Institut Curie, Centre Hospitalier)

  • Markus Metzler

    (University Hospital Erlangen)

  • Christoph Bock

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Institute of Artificial Intelligence, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna
    Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases)

  • Eleni M. Tomazou

    (St. Anna Children’s Cancer Research Institute (CCRI))

Abstract

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23445-w
    DOI: 10.1038/s41467-021-23445-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-23445-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-23445-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
    ---><---

    Citations

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


    Cited by:

    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. 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.
    3. N. Shukla & M. F. Levine & G. Gundem & D. Domenico & B. Spitzer & N. Bouvier & J. E. Arango-Ossa & D. Glodzik & J. S. Medina-Martínez & U. Bhanot & J. Gutiérrez-Abril & Y. Zhou & E. Fiala & E. Stockfi, 2022. "Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. 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.

    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:12:y:2021:i:1:d:10.1038_s41467-021-23445-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.

    We have no bibliographic references for this item. You can help adding them by using 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.