Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma

Martin Burkert; Eric Blanc; Nina Thiessen; Christiane Weber; Joern Toedling; Remo Monti; Victoria M Dombrowe; Maria Stella de Biase; Tom L Kaufmann; Kerstin Haase; Sebastian M Waszak; Angelika Eggert; Dieter Beule; Johannes H Schulte; Uwe Ohler; Roland F Schwarz

doi:10.1016/j.isci.2024.110918

Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma

iScience. 2024 Sep 10;27(10):110918. doi: 10.1016/j.isci.2024.110918. eCollection 2024 Oct 18.

Authors

Martin Burkert^{1

2}, Eric Blanc³, Nina Thiessen³, Christiane Weber¹, Joern Toedling⁴, Remo Monti², Victoria M Dombrowe², Maria Stella de Biase^{1

2}, Tom L Kaufmann^{2

5

6}, Kerstin Haase^{4

7}, Sebastian M Waszak^{8

9

10}, Angelika Eggert⁴, Dieter Beule³, Johannes H Schulte⁴, Uwe Ohler^{1

2}, Roland F Schwarz^{2

5

11}

Affiliations

¹ Department of Biology, Humboldt University, Berlin, Germany.
² Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
³ Core Unit Bioinformatics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, Berlin, Germany.
⁴ Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁵ BIFOLD - Berlin Institute for the Foundations of Learning and Data, Berlin, Germany.
⁶ Department of Electrical Engineering & Computer Science, Technische Universität Berlin, Marchstr. 23, 10587 Berlin, Germany.
⁷ German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁸ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
⁹ Department of Pediatric Research, Division of Pediatric and Adolescent Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
¹⁰ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Institute for Computational Cancer Biology (ICCB), Center for Integrated Oncology (CIO), Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Abstract

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 TERT activation, overexpression and copy-number dosage and reveal loss of imprinting at the RTL1 gene associated with poor clinical outcome. These results highlight the importance of gene dosage in key oncogenic mechanisms in neuroblastoma.

Keywords: Cell biology; Genomics; Molecular biology; Transcriptomics.