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Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

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Item Type:Article
Title:Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome
Creators Name:Hartlieb, S.A. and Sieverling, L. and Nadler-Holly, M. and Ziehm, M. and Toprak, U.H. and Herrmann, C. and Ishaque, N. and Okonechnikov, K. and Gartlgruber, M. and Park, Y.G. and Wecht, E.M. and Savelyeva, L. and Henrich, K.O. and Rosswog, C. and Fischer, M. and Hero, B. and Jones, D.T.W. and Pfaff, E. and Witt, O. and Pfister, S.M. and Volckmann, Ri. and Koster, J. and Kiesel, K. and Rippe, K. and Taschner-Mandl, S. and Ambros, P. and Brors, B. and Selbach, M. and Feuerbach, L. and Westermann, F.
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.
Keywords:Exons, Flow Cytometry, Proteome, RNA Sequence Analysis, Retrospective Studies, Telomere, Telomere Homeostasis, Western Blotting, Whole Genome Sequencing, X-linked Nuclear Protein
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:12
Number:1
Page Range:1269
Date:24 February 2021
Official Publication:https://doi.org/10.1038/s41467-021-21247-8
PubMed:View item in PubMed

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