Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome.

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.

• Authors: 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, Frank Westermann
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 1269 (02 24 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33627664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proteome
• X-linked Nuclear Protein

Topics

• Blotting, Western
• Exons (genetics)
• Flow Cytometry
• Humans
• Proteome (metabolism)
• Retrospective Studies
• Sequence Analysis, RNA (methods)
• Telomere (genetics, metabolism)
• Telomere Homeostasis (genetics)
• Whole Genome Sequencing (methods)
• X-linked Nuclear Protein (genetics)