Genomic footprints of activated telomere maintenance mechanisms in cancer

PCAWG Structural Variation Working Group; PCAWG Consortium

doi:10.1038/s41467-019-13824-9

Genomic footprints of activated telomere maintenance mechanisms in cancer

PCAWG Structural Variation Working Group
, PCAWG Consortium

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106 引用（Scopus）

摘要

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/DAXX^trunc) 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/DAXX^trunc 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.

源语言	英语
文章编号	733
期刊	Nature Communications
卷	11
期	1
DOI	https://doi.org/10.1038/s41467-019-13824-9
出版状态	已出版 - 1 12月 2020

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10.1038/s41467-019-13824-9

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title = "Genomic footprints of activated telomere maintenance mechanisms in cancer",

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 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.",

author = "\{PCAWG Structural Variation Working Group\} and \{PCAWG Consortium\} and Lina Sieverling and Chen Hong and Koser, \{Sandra D.\} and Philip Ginsbach and Kortine Kleinheinz and Barbara Hutter and Braun, \{Delia M.\} and Isidro Cort{\'e}s-Ciriano and Ruibin Xi and Rolf Kabbe and Park, \{Peter J.\} and Roland Eils and Matthias Schlesner and Akdemir, \{Kadir C.\} and Alvarez, \{Eva G.\} and Adrian Baez-Ortega and Rameen Beroukhim and Boutros, \{Paul C.\} and Bowtell, \{David D.L.\} and Benedikt Brors and Burns, \{Kathleen H.\} and Campbell, \{Peter J.\} and Kin Chan and Ken Chen and Isidro Cort{\'e}s-Ciriano and Ana Dueso-Barroso and Dunford, \{Andrew J.\} and Edwards, \{Paul A.\} and Xavier Estivill and Dariush Etemadmoghadam and Lars Feuerbach and Fink, \{J. Lynn\} and Milana Frenkel-Morgenstern and Garsed, \{Dale W.\} and Mark Gerstein and Gordenin, \{Dmitry A.\} and David Haan and Haber, \{James E.\} and Hess, \{Julian M.\} and Barbara Hutter and Marcin Imielinski and Jones, \{David T.W.\} and Ju, \{Young Seok\} and Kazanov, \{Marat D.\} and Klimczak, \{Leszek J.\} and Youngil Koh and Korbel, \{Jan O.\} and Jiayin Wang and Huanming Yang and Kai Ye",

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N2 - 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.

AB - 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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Genomic footprints of activated telomere maintenance mechanisms in cancer

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