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- Title
Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome.
- Authors
Hartlieb, Sabine A.; Sieverling, Lina; Nadler-Holly, Michal; Ziehm, Matthias; Toprak, Umut H.; Herrmann, Carl; Ishaque, Naveed; Okonechnikov, Konstantin; Gartlgruber, Moritz; Park, Young-Gyu; Wecht, Elisa Maria; Savelyeva, Larissa; Henrich, Kai-Oliver; Rosswog, Carolina; Fischer, Matthias; Hero, Barbara; Jones, David T. W.; Pfaff, Elke; Witt, Olaf; Pfister, Stefan M.
- 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. 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.
- Subjects
NEUROBLASTOMA; PROTEIN expression; GENOMES; CHROMATIN; TELOMERASE; BONE lengthening (Orthopedics)
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-21247-8