Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

Sabine Hartlieb ,Michal Nadler-Holly,Umut Toprak ,Richard Volckmann,Konstantin Okonechnikov,Stefan M Pfister,Moritz Gartlgruber,Elisa M Wecht ,Barbara Hero,Karsten Rippe,Carolina Rosswog,Lars Feuerbach,Matthias Ziehm,Sabine Taschner‐Mandl ,Peter F Ambros ,Young-Gyu Park,Olaf Witt,Naveed Ishaque,Kai-Oliver Henrich,Katharina Kiesel,David Jones ,Benedikt Brors,Matthias Selbach,Matthias Fischer,Jan Koster,Elke Pfaff,Lina Sieverling,Carl Herrmann,Larissa Savelyeva,Frank Westermann

doi:10.1038/s41467-021-21247-8

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.

Highlights

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma
ALT was significantly associated with INSS stage 4, high-risk disease, and an older age at diagnosis
Expression of the 5′−3′ exonuclease, EXO1, located on chromosome 1q43 and involved in DNA double strand break repair[41,42], telomere replication, and t-loop formation[43], was reduced in 1q42.2-deleted tumors but generally reduced in ALT-positive neuroblastomas (Supplementary Fig. 16c). In summary, this in-depth analysis revealed that ALT-positive neuroblastomas are biologically and clinically distinct from tumors with telomerase activation

Summary

Introduction

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. 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. We aim to deepen the knowledge about the biology and clinical features of ALT-positive neuroblastomas by enriching ALT tumors in the study cohort independent of ATRX mutation status. ALT-positive tumors feature mutated ATRX and/or reduced protein abundance, heterochromatic telomeric chromatin, a slow proliferative capacity, and frequent neo-telomere formation

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