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

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Abstrakt

Tytuł:: Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden.
Autorzy:: Peneder P; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Stütz AM; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Surdez D; INSERM U830, Équipe Labellisée LNCC, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, Paris, France.; Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
Krumbholz M; Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany.
Semper S; Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany.
Chicard M; INSERM U830, Équipe Labellisée LNCC, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, Paris, France.
Sheffield NC; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Pierron G; Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, Paris, France.
Lapouble E; Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, Paris, France.
Tötzl M; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Ergüner B; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Barreca D; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Rendeiro AF; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Agaimy A; Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
Boztug H; St. Anna Kinderspital, Department of Pediatrics, Medical University, Vienna, Austria.
Engstler G; St. Anna Kinderspital, Department of Pediatrics, Medical University, Vienna, Austria.
Dworzak M; St. Anna Kinderspital, Department of Pediatrics, Medical University, Vienna, Austria.
Bernkopf M; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Taschner-Mandl S; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Ambros IM; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Myklebost O; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Department of Clinical Science, University of Bergen, Bergen, Norway.
Marec-Bérard P; Pediatric Department, Hematology and Oncology Pediatric Institute, Centre Léon Bérard, Lyon, France.
Burchill SA; Children's Cancer Research Group, Leeds Institute of Medical Research, St. James's University Hospital, Leeds, UK.
Brennan B; Department of Pediatric Oncology, Royal Manchester Children's Hospital, Manchester, UK.
Strauss SJ; Department of Oncology, UCL Cancer Institute, London, UK.; Department of Oncology, University College London Hospital, London, UK.
Whelan J; Department of Oncology, University College London Hospital, London, UK.
Schleiermacher G; INSERM U830, Équipe Labellisée LNCC, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, Paris, France.
Schaefer C; University Hospital Essen, Pediatrics III, West German Cancer Centre, Essen, Germany.
Dirksen U; University Hospital Essen, Pediatrics III, West German Cancer Centre, Essen, Germany.
Hutter C; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.; St. Anna Kinderspital, Department of Pediatrics, Medical University, Vienna, Austria.
Boye K; Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
Ambros PF; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Delattre O; INSERM U830, Équipe Labellisée LNCC, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, Paris, France.; Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, Paris, France.
Metzler M; Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany.
Bock C; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. .; Institute of Artificial Intelligence, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria. .; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria. .
Tomazou EM; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria. .
Źródło:: Nature communications [Nat Commun] 2021 May 28; Vol. 12 (1), pp. 3230. Date of Electronic Publication: 2021 May 28.
Typ publikacji:: Journal Article; Observational Study; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Biomarkers, Tumor/*blood
Bone Neoplasms/*diagnosis
Circulating Tumor DNA/*blood
Sarcoma, Ewing/*diagnosis
Adolescent ; Adult ; Biomarkers, Tumor/genetics ; Bone Neoplasms/blood ; Bone Neoplasms/genetics ; Bone Neoplasms/pathology ; Case-Control Studies ; Child ; Child, Preschool ; Circulating Tumor DNA/genetics ; DNA Mutational Analysis ; Female ; Humans ; Infant ; Liquid Biopsy/methods ; Male ; Middle Aged ; Mutation ; Sarcoma, Ewing/blood ; Sarcoma, Ewing/genetics ; Sarcoma, Ewing/pathology ; Whole Genome Sequencing ; Young Adult
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Grant Information:: I 2798 Austria FWF_ Austrian Science Fund FWF; V 506 Austria FWF_ Austrian Science Fund FWF
Molecular Sequence:: ClinicalTrials.gov NCT02613962
Substance Nomenclature:: 0 (Biomarkers, Tumor)
0 (Circulating Tumor DNA)
Entry Date(s):: Date Created: 20210529 Date Completed: 20210608 Latest Revision: 20240214
Update Code:: 20240214
PubMed Central ID:: PMC8163828
DOI:: 10.1038/s41467-021-23445-w
PMID:: 34050156
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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.

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