Copy-number Dosage Regulates Telomere Maintenance and Disease-associated Pathways in Neuroblastoma

Overview

Journal iScience

Publisher Cell Press

Date 2024 Dec 5

PMID 39635126

Authors

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

Affiliations

Soon will be listed here.

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

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