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| Nature communications. 2021 Feb 24. doi: 10.1038/s41467-021-21247-8. pii: 10.1038/s41467-021-21247-8 |
| Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome. |
| Hartlieb SA1, Sieverling L2, Nadler-Holly M3, Ziehm M4, Toprak UH5, Herrmann C6, Ishaque N7, Okonechnikov K8, Gartlgruber M9, Park YG10, Wecht EM11, Savelyeva L12, Henrich KO13, Rosswog C14, Fischer M15, Hero B16, Jones DTW17, Pfaff E18, Witt O19, Pfister SM20, Volckmann R21, Koster J22, Kiesel K23, Rippe K24, Taschner-Mandl S25, Ambros P26, Brors B27, Selbach M28, Feuerbach L29, Westermann F30 |
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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. |
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Publikations ID: 33627664 Quelle: öffnen |
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