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Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

Author

Listed:
  • Sabine A. Hartlieb

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Lina Sieverling

    (Heidelberg University
    German Cancer Consortium (DKTK)
    National Center for Tumor Diseases (NCT))

  • Michal Nadler-Holly

    (Max Delbrück Center for Molecular Medicine)

  • Matthias Ziehm

    (Max Delbrück Center for Molecular Medicine)

  • Umut H. Toprak

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Carl Herrmann

    (Medical Faculty Heidelberg and BioQuant)

  • Naveed Ishaque

    (Berlin Institute of Health (BIH)
    Charité – Universitätsmedizin Berlin)

  • Konstantin Okonechnikov

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Moritz Gartlgruber

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Young-Gyu Park

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Elisa Maria Wecht

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Larissa Savelyeva

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Kai-Oliver Henrich

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Carolina Rosswog

    (University Children’s Hospital of Cologne, Medical Faculty)

  • Matthias Fischer

    (University Children’s Hospital of Cologne, Medical Faculty
    University of Cologne
    University of Cologne)

  • Barbara Hero

    (University of Cologne)

  • David T. W. Jones

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

  • Elke Pfaff

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    University Hospital)

  • Olaf Witt

    (Hopp Children’s Cancer Center (KiTZ)
    University Hospital
    German Cancer Research Center (DKFZ))

  • Stefan M. Pfister

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    University Hospital)

  • Richard Volckmann

    (Department of Oncogenomics Amsterdam University Medical Centers (AUMC))

  • Jan Koster

    (Department of Oncogenomics Amsterdam University Medical Centers (AUMC))

  • Katharina Kiesel

    (German Cancer Research Center (DKFZ) and BioQuant)

  • Karsten Rippe

    (German Cancer Research Center (DKFZ) and BioQuant)

  • Sabine Taschner-Mandl

    (St Anna Children’s Cancer Research Institute)

  • Peter Ambros

    (St Anna Children’s Cancer Research Institute)

  • Benedikt Brors

    (German Cancer Consortium (DKTK))

  • Matthias Selbach

    (Max Delbrück Center for Molecular Medicine
    Charité – Universitätsmedizin Berlin)

  • Lars Feuerbach

    (German Cancer Consortium (DKTK))

  • Frank Westermann

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ))

Abstract

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.

Suggested Citation

  • Sabine A. Hartlieb & Lina Sieverling & Michal Nadler-Holly & Matthias Ziehm & Umut H. Toprak & Carl Herrmann & Naveed Ishaque & Konstantin Okonechnikov & Moritz Gartlgruber & Young-Gyu Park & Elisa Ma, 2021. "Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21247-8
    DOI: 10.1038/s41467-021-21247-8
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    Cited by:

    1. Steffen Fuchs & Clara Danßmann & Filippos Klironomos & Annika Winkler & Jörg Fallmann & Louisa-Marie Kruetzfeldt & Annabell Szymansky & Julian Naderi & Stephan H. Bernhart & Laura Grunewald & Konstant, 2023. "Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. 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.
    3. 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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