Universität zu Köln

Meeser, Alina, Bartenhagen, Christoph, Werr, Lisa, Hellmann, Anna-Maria, Kahlert, Yvonne, Hemstedt, Nadine, Nuernberg, Peter, Altmueller, Janine, Ackermann, Sandra, Hero, Barbara, Simon, Thorsten ORCID: 0000-0002-3425-8451, Peifer, Martin ORCID: 0000-0002-5243-5503, Fischer, Matthias and Rosswog, Carolina (2022). Reliable assessment of telomere maintenance mechanisms in neuroblastoma. Cell Biosci., 12 (1). LONDON: BMC. ISSN 2045-3701

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Abstract

Background Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. Methods Whole genome sequencing (WGS) data of 68 primary neuroblastoma samples were analyzed. Telomere length was calculated from WGS data or by telomere restriction fragment analysis (n = 39). ALT was assessed by C-circle assay (CCA, n = 67) and detection of ALT-associated PML nuclear bodies (APB) by combined fluorescence in situ hybridization and immunofluorescence staining (n = 68). RNA sequencing was performed (n = 64) to determine expression of TERT and telomeric long non-coding RNA (TERRA). Telomerase activity was examined by telomerase repeat amplification protocol (TRAP, n = 15). Results Tumors were considered as telomerase-positive if they harbored a TERT rearrangement, MYCN amplification or high TERT expression (45.6%, 31/68), and ALT-positive if they were positive for APB and CCA (19.1%, 13/68). If all these markers were absent, tumors were considered TMM-negative (25.0%, 17/68). According to these criteria, the majority of samples were classified unambiguously (89.7%, 61/68). Assessment of additional ALT-associated parameters clarified the TMM status of the remaining seven cases with high likelihood: ALT-positive tumors had higher TERRA expression, longer telomeres, more telomere insertions, a characteristic pattern of telomere variant repeats, and were associated with ATRX mutations. Conclusions We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Meeser, Alina UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartenhagen, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Werr, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Hellmann, Anna-Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Kahlert, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED Hemstedt, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Ackermann, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Hero, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, Thorsten UNSPECIFIED orcid.org/0000-0002-3425-8451 UNSPECIFIED Peifer, Martin UNSPECIFIED orcid.org/0000-0002-5243-5503 UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosswog, Carolina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-686044
DOI:	10.1186/s13578-022-00896-2
Journal or Publication Title:	Cell Biosci.
Volume:	12
Number:	1
Date:	2022
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	2045-3701
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VARIANT REPEATS; LENGTH; CLASSIFICATION; CANCER; REARRANGEMENTS; MUTATIONS; CELLS Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68604