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Reliable assessment of telomere maintenance mechanisms in neuroblastoma.
Meeser, Alina; Bartenhagen, Christoph; Werr, Lisa; Hellmann, Anna-Maria; Kahlert, Yvonne; Hemstedt, Nadine; Nürnberg, Peter; Altmüller, Janine; Ackermann, Sandra; Hero, Barbara; Simon, Thorsten; Peifer, Martin; Fischer, Matthias; Rosswog, Carolina.
Afiliação
  • Meeser A; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
  • Bartenhagen C; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
  • Werr L; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
  • Hellmann AM; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
  • Kahlert Y; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
  • Hemstedt N; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
  • Nürnberg P; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
  • Altmüller J; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
  • Ackermann S; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
  • Hero B; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
  • Simon T; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
  • Peifer M; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
  • Fischer M; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
  • Rosswog C; Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Cell Biosci ; 12(1): 160, 2022 Sep 24.
Article em En | MEDLINE | ID: mdl-36153564
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Guideline Idioma: En Revista: Cell Biosci Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Guideline Idioma: En Revista: Cell Biosci Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha