Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

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 Maria Wecht, Larissa Savelyeva, Kai-Oliver Henrich, Carolina Rosswog, Matthias Fischer, Barbara Hero, David T. W. Jones, Elke Pfaff, Olaf Witt, Stefan M. Pfister, Richard Volckmann, Jan Koster, Katharina Kiesel, Karsten Rippe, Sabine Taschner-Mandl, Peter Ambros, Benedikt Brors, Matthias Selbach, Lars Feuerbach and Frank Westermann ()
Additional contact information
Sabine A. Hartlieb: Hopp Children’s Cancer Center (KiTZ)
Lina Sieverling: Heidelberg University
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)
Carl Herrmann: Medical Faculty Heidelberg and BioQuant
Naveed Ishaque: Berlin Institute of Health (BIH)
Konstantin Okonechnikov: Hopp Children’s Cancer Center (KiTZ)
Moritz Gartlgruber: Hopp Children’s Cancer Center (KiTZ)
Young-Gyu Park: Hopp Children’s Cancer Center (KiTZ)
Elisa Maria Wecht: Hopp Children’s Cancer Center (KiTZ)
Larissa Savelyeva: Hopp Children’s Cancer Center (KiTZ)
Kai-Oliver Henrich: Hopp Children’s Cancer Center (KiTZ)
Carolina Rosswog: University Children’s Hospital of Cologne, Medical Faculty
Matthias Fischer: University Children’s Hospital of Cologne, Medical Faculty
Barbara Hero: University of Cologne
David T. W. Jones: Hopp Children’s Cancer Center (KiTZ)
Elke Pfaff: Hopp Children’s Cancer Center (KiTZ)
Olaf Witt: Hopp Children’s Cancer Center (KiTZ)
Stefan M. Pfister: Hopp Children’s Cancer Center (KiTZ)
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
Lars Feuerbach: German Cancer Consortium (DKTK)
Frank Westermann: Hopp Children’s Cancer Center (KiTZ)

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21247-8

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DOI: 10.1038/s41467-021-21247-8

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