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| Item Type: | Article |
|---|---|
| Title: | Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome |
| Creators: |
Hartlieb, S.A.  ORCID: https://orcid.org/0000-0003-3746-7010, Sieverling, L. ORCID: https://orcid.org/0000-0002-0595-4976, Nadler-Holly, M., Ziehm, M. ORCID: https://orcid.org/0000-0001-7074-4054, Toprak, U.H., Herrmann, C. ORCID: https://orcid.org/0000-0003-4989-4722, Ishaque, N. ORCID: https://orcid.org/0000-0002-8426-901X, Okonechnikov, K., Gartlgruber, M., Park, Y.G., Wecht, E.M., Savelyeva, L., Henrich, K.O., Rosswog, C., Fischer, M. ORCID: https://orcid.org/0000-0003-1363-1242, Hero, B., Jones, D.T.W., Pfaff, E., Witt, O., Pfister, S.M., Volckmann, Ri., Koster, J. ORCID: https://orcid.org/0000-0002-0890-7585, Kiesel, K., Rippe, K. ORCID: https://orcid.org/0000-0001-9951-9395, Taschner-Mandl, S. ORCID: https://orcid.org/0000-0002-1439-5301, Ambros, P., Brors, B. ORCID: https://orcid.org/0000-0001-5940-3101, Selbach, M. ORCID: https://orcid.org/0000-0003-2454-8751, Feuerbach, L. ORCID: https://orcid.org/0000-0003-1503-437X and Westermann, F.
|
| 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. |
| Keywords: | Exons, Flow Cytometry, Proteome, RNA Sequence Analysis, Retrospective Studies, Telomere, Telomere Homeostasis, Western Blotting, Whole Genome Sequencing, X-linked Nuclear Protein |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 12 |
| Number: | 1 |
| Page Range: | 1269 |
| Date: | 24 February 2021 |
| Official Publication: | https://doi.org/10.1038/s41467-021-21247-8 |
| PubMed: | View item in PubMed |
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