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

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 Barreca, André F. Rendeiro, Abbas Agaimy, Heidrun Boztug, Gernot Engstler, Michael Dworzak, Marie Bernkopf, Sabine Taschner-Mandl, Inge M. Ambros, Ola Myklebost, Perrine Marec-Bérard, Susan Ann Burchill, Bernadette Brennan, Sandra J. Strauss, Jeremy Whelan, Gudrun Schleiermacher, Christiane Schaefer, Uta Dirksen, Caroline Hutter, Kjetil Boye, Peter F. Ambros, Olivier Delattre, Markus Metzler, Christoph Bock () and Eleni M. Tomazou ()
Additional contact information
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
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
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
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)
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
Markus Metzler: University Hospital Erlangen
Christoph Bock: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Eleni M. Tomazou: St. Anna Children’s Cancer Research Institute (CCRI)

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23445-w

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