TY - JOUR
T1 - Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome
AU - Hartlieb, Sabine A.
AU - Sieverling, Lina
AU - Nadler-Holly, Michal
AU - Ziehm, Matthias
AU - Toprak, Umut H.
AU - Herrmann, Carl
AU - Ishaque, Naveed
AU - Okonechnikov, Konstantin
AU - Gartlgruber, Moritz
AU - Park, Young-Gyu
AU - Wecht, Elisa Maria
AU - Savelyeva, Larissa
AU - Henrich, Kai-Oliver
AU - Rosswog, Carolina
AU - Fischer, Matthias
AU - Hero, Barbara
AU - Jones, David T. W.
AU - Pfaff, Elke
AU - Witt, Olaf
AU - Pfister, Stefan M.
AU - Volckmann, Richard
AU - Koster, Jan
AU - Kiesel, Katharina
AU - Rippe, Karsten
AU - Taschner-Mandl, Sabine
AU - Ambros, Peter
AU - Brors, Benedikt
AU - Selbach, Matthias
AU - Feuerbach, Lars
AU - Westermann, Frank
N1 - Funding Information: We thank all the patients and their families for consenting to the use of tumor material for this study. Additionally, we want to thank the Neuroblastoma Biobank and the INFORM incoming lab for the support of the study. We acknowledge the DKFZ Genomics and Proteomics sequencing core facility headed by Stefan Wolf for the excellent high-throughput sequencing service and the DKFZ Omics IT and Data Management Core Facility (ODCF) headed by Ivo Buchhalter for data management and data processing. Especially, we thank Ingrid Scholz from the DKFZ Omics IT and Data Management Core Facility (ODCF) for great support with the data upload. We thank Carolin Meyer for providing bioinformatic tools and scripts for copy number analysis. We thank the lab of Irina Solovei for support with FISH analysis of cryosections. This project was supported by the Berlin Institute of Health within the collaborative research project TERMINATE-NB (CRG04) to MS. Furthermore, this project was supported by the German Ministry of Science and Education (BMBF) within the project SYSMED-NB (FW and MS), by the DKFZ-Heidelberg Center for Personalized Oncology (HIPO) within the HIPO2-K09R project (FW), by the Deutsche Krebshilfe within the project ENABLE (FW) and by the National Center for Tumor Disease within the project NCT 3.0-ENHANCE (FW). The project has been co-funded by the Vienna Science and Technology fund (WWTF) and the City of Vienna through the project LS18-111. Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85101548940&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-021-21247-8
DO - https://doi.org/10.1038/s41467-021-21247-8
M3 - Article
C2 - 33627664
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1269
ER -