Universität zu Köln

Roderwieser, Andrea, Sand, Frederik, Walter, Esther, Fischer, Janina, Gecht, Judith, Bartenhagen, Christoph, Ackermann, Sandra, Otte, Felix, Welte, Anne, Kahlert, Yvonne, Lieberz, Daniela, Hertwig, Falk, Reinhardt, H. Christian, Simon, Thorsten, Peifer, Martin, Ortmann, Monika, Buettner, Reinhard, Hero, Barbara, O'Sullivan, Roderick J., Berthold, Frank and Fischer, Matthias (2019). Telomerase Is a Prognostic Marker of Poor Outcome and a Therapeuctic Target in Neuroblastoma. JCO Precis. Oncol., 3. ALEXANDRIA: AMER SOC CLINICAL ONCOLOGY. ISSN 2473-4284

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Abstract

PURPOSE Telomere maintenance is a hallmark of high-risk neuroblastoma; however, the contribution of telomerase and alternative lengthening of telomeres (ALT) to clinical phenotypes has remained unclear. We aimed to determine the clinical relevance of telomerase activation versus ALT as biomarkers in pretreatment neuroblastoma and to assess the potential value of telomerase as a therapeutic target. MATERIALS AND METHODS The genomic status of TERT and MYCN was assessed in 457 pretreatment neuroblastomas by fluorescence in situ hybridization. ALT was examined in 273 of 457 tumors by detection of ALT-associated promyelocytic leukemia nuclear bodies, and TERT expression was determined by microarrays in 223 of these. Cytotoxic effects of telomerase-interacting compounds were analyzed in neuroblastoma cell lines in vitro and in vivo. RESULTS We detected TERT rearrangements in 46 of 457 cases (10.1%), MYCN amplification in 93 of 457 cases (20.4%), and elevated TERT expression in tumors lacking TERT or MYCN alterations in 10 of 223 cases (4.5%). ALT activation was found in 49 of 273 cases (17.9%). All these alterations occurred almost mutually exclusively and were associated with unfavorable prognostic variables and adverse outcome. The presence of activated telomerase (ie, TERT rearrangements, MYCN amplification, or high TERT expression without these alterations) was associated with poorest overall survival and was an independent prognostic marker in multi-variable analyses. We also found that the telomerase-interacting compound 6-thio-2'-deoxyguanosine effectively inhibited viability and proliferation of neuroblastoma cells bearing activated telomerase. Similarly, tumor growth was strongly impaired upon 6-thio-2'-deoxyguanosine treatment in telomerase-positive neuroblastoma xenografts in mice. CONCLUSION Our data suggest telomerase activation and ALT define distinct neuroblastoma subgroups with adverse outcome and that telomerase may represent a promising therapeutic target in many high-risk neuroblastomas. (C) 2019 by American Society of Clinical Oncology

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Roderwieser, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Sand, Frederik UNSPECIFIED UNSPECIFIED UNSPECIFIED Walter, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Janina UNSPECIFIED UNSPECIFIED UNSPECIFIED Gecht, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartenhagen, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Ackermann, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Otte, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Welte, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Kahlert, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED Lieberz, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Hertwig, Falk UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, H. Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Ortmann, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Hero, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Sullivan, Roderick J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Berthold, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-141274
DOI:	10.1200/PO.19.00072
Journal or Publication Title:	JCO Precis. Oncol.
Volume:	3
Date:	2019
Publisher:	AMER SOC CLINICAL ONCOLOGY
Place of Publication:	ALEXANDRIA
ISSN:	2473-4284
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language C-MYC; EXPRESSION; GENE; CLASSIFICATION; ALK; REARRANGEMENTS; INHIBITION; ACTIVATION; MUTATIONS; INDUCTION Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14127