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Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions

Author

Listed:
  • Karin Schmelz

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ))

  • Joern Toedling

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ))

  • Matt Huska

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Maja C. Cwikla

    (Charité—Universitätsmedizin Berlin
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Louisa-Marie Kruetzfeldt

    (Charité—Universitätsmedizin Berlin)

  • Jutta Proba

    (Charité—Universitätsmedizin Berlin)

  • Peter F. Ambros

    (St. Anna Kinderkrebsforschung)

  • Inge M. Ambros

    (St. Anna Kinderkrebsforschung)

  • Sengül Boral

    (Charité—Universitätsmedizin Berlin)

  • Marco Lodrini

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ))

  • Celine Y. Chen

    (Charité—Universitätsmedizin Berlin
    Experimental and Clinical Research Center (ECRC) of the Charité and Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Martin Burkert

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Dennis Guergen

    (Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO))

  • Annabell Szymansky

    (Charité—Universitätsmedizin Berlin)

  • Kathy Astrahantseff

    (Charité—Universitätsmedizin Berlin)

  • Annette Kuenkele

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ)
    Berlin Institute of Health (BIH))

  • Kerstin Haase

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ)
    Berlin Institute of Health (BIH))

  • Matthias Fischer

    (Department of Experimental Pediatric Oncology, Medical Faculty, University Children’s Hospital of Cologne
    University of Cologne)

  • Hedwig E. Deubzer

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ)
    Experimental and Clinical Research Center (ECRC) of the Charité and Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Falk Hertwig

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ))

  • Patrick Hundsdoerfer

    (Charité—Universitätsmedizin Berlin
    Helios Klinikum Berlin-Buch)

  • Anton G. Henssen

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ)
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Roland F. Schwarz

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    BIFOLD—Berlin Institute for the Foundations of Learning and Data)

  • Johannes H. Schulte

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ)
    Berlin Institute of Health (BIH))

  • Angelika Eggert

    (Charité—Universitätsmedizin Berlin
    The German Cancer Consortium (DKTK), Partner Site Berlin
    The German Cancer Research Center (DKFZ)
    Berlin Institute of Health (BIH))

Abstract

Intratumour heterogeneity is a major cause of treatment failure in cancer. We present in-depth analyses combining transcriptomic and genomic profiling with ultra-deep targeted sequencing of multiregional biopsies in 10 patients with neuroblastoma, a devastating childhood tumour. We observe high spatial and temporal heterogeneity in somatic mutations and somatic copy-number alterations which are reflected on the transcriptomic level. Mutations in some druggable target genes including ALK and FGFR1 are heterogeneous at diagnosis and/or relapse, raising the issue whether current target prioritization and molecular risk stratification procedures in single biopsies are sufficiently reliable for therapy decisions. The genetic heterogeneity in gene mutations and chromosome aberrations observed in deep analyses from patient courses suggest clonal evolution before treatment and under treatment pressure, and support early emergence of metastatic clones and ongoing chromosomal instability during disease evolution. We report continuous clonal evolution on mutational and copy number levels in neuroblastoma, and detail its implications for therapy selection, risk stratification and therapy resistance.

Suggested Citation

  • Karin Schmelz & Joern Toedling & Matt Huska & Maja C. Cwikla & Louisa-Marie Kruetzfeldt & Jutta Proba & Peter F. Ambros & Inge M. Ambros & Sengül Boral & Marco Lodrini & Celine Y. Chen & Martin Burker, 2021. "Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26870-z
    DOI: 10.1038/s41467-021-26870-z
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    1. Jenny Karlsson & Hiroaki Yasui & Adriana Mañas & Natalie Andersson & Karin Hansson & Kristina Aaltonen & Caroline Jansson & Geoffroy Durand & Naveen Ravi & Michele Ferro & Minjun Yang & Subhayan Chatt, 2024. "Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Irfete S. Fetahu & Wolfgang Esser-Skala & Rohit Dnyansagar & Samuel Sindelar & Fikret Rifatbegovic & Andrea Bileck & Lukas Skos & Eva Bozsaky & Daria Lazic & Lisa Shaw & Marcus Tötzl & Dora Tarlungean, 2023. "Single-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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