| Literature DB >> 33627664 |
Sabine A Hartlieb1,2,3, Lina Sieverling3,4,5, Michal Nadler-Holly6, Matthias Ziehm6, Umut H Toprak1,2, Carl Herrmann7, Naveed Ishaque8,9, Konstantin Okonechnikov1,10, Moritz Gartlgruber1,2, Young-Gyu Park1,2, Elisa Maria Wecht1,2, Larissa Savelyeva1,2, Kai-Oliver Henrich1,2, Carolina Rosswog11, Matthias Fischer11,12,13, Barbara Hero13, David T W Jones1,14, Elke Pfaff1,10,15, Olaf Witt1,15,16, Stefan M Pfister1,10,15, Richard Volckmann17, Jan Koster17, Katharina Kiesel18, Karsten Rippe18, Sabine Taschner-Mandl19, Peter Ambros19, Benedikt Brors4, Matthias Selbach6,9, Lars Feuerbach4, Frank Westermann20,21.
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.Entities:
Year: 2021 PMID： 33627664 DOI： 10.1038/s41467-021-21247-8
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919