Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma
Telomere maintenance in neuroblastoma is linked to poor outcome and caused by either telomerase reverse transcriptase (TERT) activation or through alternative lengthening of telomeres (ALT). In contrast to TERT activation, commonly caused by genomic rearrangements or MYCN amplification, ALT is less well understood. Alterations at the ATRX locus are key drivers of ALT but only present in ∼50% of ALT tumors. To identify potential new pathways to telomere maintenance, we investigate allele-specific gene dosage effects from whole genomes and transcriptomes in 115 primary neuroblastomas. We show that copy-number dosage deregulates telomere maintenance, genomic stability, and neuronal pathways and identify upregulation of variants of histone H3 and H2A as a potential alternative pathway to ALT. We investigate the interplay between <i>TERT</i> activation, overexpression and copy-number dosage and reveal loss of imprinting at the <i>RTL1</i> gene associated with poor clinical outcome. These results highlight the importance of gene dosage in key oncogenic mechanisms in neuroblastoma.
Authors
- Uwe Ohler (ORCID: https://orcid.org/0000-0002-0881-3116)
- Maria Stella de Biase (ORCID: https://orcid.org/0000-0003-0383-5161)
- Nina Thiessen
- Martin Burkert (ORCID: https://orcid.org/0000-0002-6721-9985)
- Eric Blanc (ORCID: https://orcid.org/0000-0002-4369-0254)
- Christiane Weber (ORCID: https://orcid.org/0000-0001-5446-8707)
- Johannes H. Schulte (ORCID: https://orcid.org/0000-0003-0671-1201)
- Tom L. Kaufmann (ORCID: https://orcid.org/0000-0003-4374-1338)
- Sebastian M. Waszak (ORCID: https://orcid.org/0000-0003-3042-9521)
- Angelika Eggert (ORCID: https://orcid.org/0000-0003-3476-8184)
- Remo Monti (ORCID: https://orcid.org/0000-0002-6354-8319)
- Dieter Beule (ORCID: https://orcid.org/0000-0002-3284-0632)
- Roland F. Schwarz (ORCID: https://orcid.org/0000-0001-9155-4268)
- Joern Toedling (ORCID: https://orcid.org/0000-0003-1471-1295)
- Kerstin Haase (ORCID: https://orcid.org/0000-0002-0944-5618)
- Victoria M Dombrowe (ORCID: https://orcid.org/0000-0002-1466-1518)
Institutions
- Oslo University Hospital (NO)
- German Cancer Research Center (DE)
- University of California, San Francisco (US)
- University of Cologne (DE)
- University of Oslo (NO)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- Humboldt-Universität zu Berlin (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- University Hospital Cologne (DE)
- Berlin Institute for the Foundations of Learning and Data (DE)
- Technische Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- iScience
- Published
- 2024-09-10
- DOI
- https://doi.org/10.1016/j.isci.2024.110918
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Berlin Institute of Health