Journal Article

Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

Herrmann, Carl, Rippe, Karsten, Gartlgruber, Moritz, Toprak, Umut H., Sieverling, Lina, Wecht, Elisa Maria, Koster, Jan, Hartlieb, Sabine A., Hero, Barbara, Ishaque, Naveed, Westermann, Frank, Savelyeva, Larissa, Ziehm, Matthias, Witt, Olaf, Kiesel, Katharina, Park, Young-Gyu, Okonechnikov, Konstantin, Feuerbach, Lars, Jones, David T. W., Nadler-Holly, Michal, Pfister, Stefan M., Rosswog, Carolina, Volckmann, Richard, Henrich, Kai-Oliver, Fischer, Matthias, Pfaff, Elke, Ambros, Peter, Selbach, Matthias, Brors, Benedikt, Taschner-Mandl, Sabine

2021

Overview

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. Alternative lengthening of telomeres (ALT) is associated with a poor outcome in neuroblastoma. Here, the authors find that ALT is associated with mutated ATRX and/or reduced protein abundance, frequent telomeric repeat loci and heterochromatic telomeric chromatin.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/15 / 38/39 / 45 / 45/23 / 45/91 / 631/67/1678 / 631/67/2332 / 631/67/69 / 82/58 / Blotting, Western / Childhood / Children / Chromatin / Daxx protein / Exons - genetics / Flow Cytometry / Genomes / Histones / Humanities and Social Sciences / Humans / Loci / multidisciplinary / Mutation / Neuroblastoma / Population studies / Proteins / Proteome - metabolism / Proteomes / Retrospective Studies / Science / Science (multidisciplinary) / Sequence Analysis, RNA - methods / Telomerase / Telomere - genetics / Telomere - metabolism / Telomere Homeostasis - genetics / Telomeres / Tumors / Whole Genome Sequencing - methods / X-linked Nuclear Protein - genetics