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Genomic footprints of activated telomere maintenance mechanisms in cancer

Sieverling, Lina ; Hong, Chen ; Koser, Sandra D ; Ginsbach, Philip ; Kleinheinz, Kortine ; Hutter, Barbara ; Braun, Delia M ; Cortés-Ciriano, Isidro ; Xi, Ruibin and Kabbe, Rolf , et al. (2020) In Nature Communications 11.
Abstract

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor... (More)

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.

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publication status
published
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keywords
Case-Control Studies, Co-Repressor Proteins/genetics, Genome, Human, Humans, Molecular Chaperones/genetics, Mutation, Neoplasms/genetics, RNA, Long Noncoding, Repetitive Sequences, Nucleic Acid, Telomerase/genetics, Telomere/genetics, Whole Genome Sequencing, X-linked Nuclear Protein/genetics
in
Nature Communications
volume
11
article number
733
pages
13 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85079058593
  • pmid:32024817
ISSN
2041-1723
DOI
10.1038/s41467-019-13824-9
language
English
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yes
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849ffdea-c3b6-4e87-9f82-a38a5ad676fd
date added to LUP
2023-01-05 13:52:14
date last changed
2024-04-18 09:36:34
@article{849ffdea-c3b6-4e87-9f82-a38a5ad676fd,
  abstract     = {{<p>Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.</p>}},
  author       = {{Sieverling, Lina and Hong, Chen and Koser, Sandra D and Ginsbach, Philip and Kleinheinz, Kortine and Hutter, Barbara and Braun, Delia M and Cortés-Ciriano, Isidro and Xi, Ruibin and Kabbe, Rolf and Park, Peter J and Eils, Roland and Schlesner, Matthias and Brors, Benedikt and Rippe, Karsten and Jones, David T W and Feuerbach, Lars}},
  issn         = {{2041-1723}},
  keywords     = {{Case-Control Studies; Co-Repressor Proteins/genetics; Genome, Human; Humans; Molecular Chaperones/genetics; Mutation; Neoplasms/genetics; RNA, Long Noncoding; Repetitive Sequences, Nucleic Acid; Telomerase/genetics; Telomere/genetics; Whole Genome Sequencing; X-linked Nuclear Protein/genetics}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Genomic footprints of activated telomere maintenance mechanisms in cancer}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-13824-9}},
  doi          = {{10.1038/s41467-019-13824-9}},
  volume       = {{11}},
  year         = {{2020}},
}