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

German Cancer Research Center
Heidelberg University
Harvard University
University of Cambridge
Peking University
University of Texas MD Anderson Cancer Center
University of Santiago de Compostela
University of Vigo
Broad Institute
Dana-Farber Cancer Institute
Ontario Institute for Cancer Research
University of California at Los Angeles
University of Toronto
Peter Maccallum Cancer Centre
University of Melbourne
Johns Hopkins University
Cambridge University Hospitals NHS Foundation Trust
Wellcome Trust Genome Campus
University of Ottawa
Barcelona Supercomputing Center (BSC)
Cancer Research UK Cambridge Institute
Barcelona Institute of Science and Technology (BIST)
Quantitative Genomics Laboratories (qGenomics)
University of Queensland
Bar-Ilan University
Yale University
National Institutes of Health
University of California Santa Cruz
Brandeis University
Massachusetts General Hospital
Cornell University
New York Genome Center
Hopp Children’s Cancer Center (KiTZ)
Korea Advanced Institute of Science and Technology
Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Russian Academy of Sciences
Skolkovo Institute of Science and Technology
Seoul National University
European Molecular Biology Laboratory

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114 Atsauces (Scopus)

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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.

Oriģinālvaloda	Angļu
Raksta numurs	733
Žurnāls	Nature Communications
Sējums	11
Izdevuma numurs	1
DOIs	https://doi.org/10.1038/s41467-019-13824-9
Publikācijas statuss	Publicēts - 1 dec. 2020

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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 Kiran Kumar and Alvis Brāzma and Juris Vīksna",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13824-9",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - Genomic footprints of activated telomere maintenance mechanisms in cancer

AU - PCAWG Structural Variation Working Group

AU - PCAWG Consortium

AU - Sieverling, Lina

AU - Hong, Chen

AU - Koser, Sandra D.

AU - Ginsbach, Philip

AU - Kleinheinz, Kortine

AU - Hutter, Barbara

AU - Braun, Delia M.

AU - Cortés-Ciriano, Isidro

AU - Xi, Ruibin

AU - Kabbe, Rolf

AU - Park, Peter J.

AU - Eils, Roland

AU - Schlesner, Matthias

AU - Akdemir, Kadir C.

AU - Alvarez, Eva G.

AU - Baez-Ortega, Adrian

AU - Beroukhim, Rameen

AU - Boutros, Paul C.

AU - Bowtell, David D.L.

AU - Brors, Benedikt

AU - Burns, Kathleen H.

AU - Campbell, Peter J.

AU - Chan, Kin

AU - Chen, Ken

AU - Cortés-Ciriano, Isidro

AU - Dueso-Barroso, Ana

AU - Dunford, Andrew J.

AU - Edwards, Paul A.

AU - Estivill, Xavier

AU - Etemadmoghadam, Dariush

AU - Feuerbach, Lars

AU - Fink, J. Lynn

AU - Frenkel-Morgenstern, Milana

AU - Garsed, Dale W.

AU - Gerstein, Mark

AU - Gordenin, Dmitry A.

AU - Haan, David

AU - Haber, James E.

AU - Hess, Julian M.

AU - Hutter, Barbara

AU - Imielinski, Marcin

AU - Jones, David T.W.

AU - Ju, Young Seok

AU - Kazanov, Marat D.

AU - Klimczak, Leszek J.

AU - Koh, Youngil

AU - Korbel, Jan O.

AU - Kumar, Kiran

AU - Brāzma, Alvis

AU - Vīksna, Juris

PY - 2020/12/1

Y1 - 2020/12/1

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.

UR - https://www.nature.com/articles/s41467-019-13824-9

UR - https://www.scopus.com/pages/publications/85079058593

U2 - 10.1038/s41467-019-13824-9

DO - 10.1038/s41467-019-13824-9

M3 - Article

C2 - 32024817

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 733

ER -

Genomic footprints of activated telomere maintenance mechanisms in cancer

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