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. PfisterRichard Volckmann, Jan Koster, Katharina Kiesel, Karsten Rippe, Sabine Taschner-Mandl, Peter Ambros, Benedikt Brors, Matthias Selbach, Lars Feuerbach, Frank Westermann

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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.
Original languageEnglish
Article number1269
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - 1 Dec 2021

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