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Genomic footprints of activated telomere maintenance mechanisms in cancer

Author

Listed:
  • Lina Sieverling

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Chen Hong

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Sandra D. Koser

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Philip Ginsbach

    (German Cancer Research Center (DKFZ))

  • Kortine Kleinheinz

    (German Cancer Research Center (DKFZ)
    Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant)

  • Barbara Hutter

    (German Cancer Consortium (DKTK)
    National Center for Tumor Diseases (NCT) Heidelberg
    German Cancer Research Center (DKFZ))

  • Delia M. Braun

    (Heidelberg University
    German Cancer Research Center (DKFZ) and BioQuant)

  • Isidro Cortés-Ciriano

    (Harvard Medical School
    Centre for Molecular Science Informatics, University of Cambridge
    Ludwig Center at Harvard Medical School)

  • Ruibin Xi

    (Peking University)

  • Rolf Kabbe

    (German Cancer Research Center (DKFZ))

  • Peter J. Park

    (Harvard Medical School
    Ludwig Center at Harvard Medical School)

  • Roland Eils

    (German Cancer Research Center (DKFZ)
    Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant)

  • Matthias Schlesner

    (German Cancer Research Center (DKFZ))

  • Benedikt Brors

    (German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK)
    National Center for Tumor Diseases (NCT) Heidelberg)

  • Karsten Rippe

    (German Cancer Research Center (DKFZ) and BioQuant)

  • David T. W. Jones

    (Hopp Children’s Cancer Center (KiTZ)
    Pediatric Glioma Research Group, German Cancer Research Center (DKFZ))

  • Lars Feuerbach

    (German Cancer Research Center (DKFZ))

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.

Suggested Citation

  • Lina Sieverling & Chen Hong & Sandra D. Koser & Philip Ginsbach & Kortine Kleinheinz & Barbara Hutter & Delia M. Braun & Isidro Cortés-Ciriano & Ruibin Xi & Rolf Kabbe & Peter J. Park & Roland Eils & , 2020. "Genomic footprints of activated telomere maintenance mechanisms in cancer," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13824-9
    DOI: 10.1038/s41467-019-13824-9
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    Cited by:

    1. Angela M. Hinchie & Samantha L. Sanford & Kelly E. Loughridge & Rachel M. Sutton & Anishka H. Parikh & Agustin A. Gil Silva & Daniel I. Sullivan & Pattra Chun-On & Matthew R. Morrell & John F. McDyer , 2024. "A persistent variant telomere sequence in a human pedigree," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Francesc Muyas & Manuel José Gómez Rodriguez & Rita Cascão & Angela Afonso & Carolin M. Sauer & Claudia C. Faria & Isidro Cortés-Ciriano & Ignacio Flores, 2024. "The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Julie Livingstone & Yu-Jia Shiah & Takafumi N. Yamaguchi & Lawrence E. Heisler & Vincent Huang & Robert Lesurf & Tsumugi Gebo & Benjamin Carlin & Stefan Eng & Erik Drysdale & Jeffrey Green & Theodorus, 2021. "The telomere length landscape of prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. Junyeop Lee & Keewon Sung & So Young Joo & Jun-Hyeon Jeong & Seong Keun Kim & Hyunsook Lee, 2022. "Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Philip S. Robinson & Laura E. Thomas & Federico Abascal & Hyunchul Jung & Luke M. R. Harvey & Hannah D. West & Sigurgeir Olafsson & Bernard C. H. Lee & Tim H. H. Coorens & Henry Lee-Six & Laura Butlin, 2022. "Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Fei Li & Yizhe Wang & Inah Hwang & Ja-Young Jang & Libo Xu & Zhong Deng & Eun Young Yu & Yiming Cai & Caizhi Wu & Zhenbo Han & Yu-Han Huang & Xiangao Huang & Ling Zhang & Jun Yao & Neal F. Lue & Paul , 2023. "Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. N. Shukla & M. F. Levine & G. Gundem & D. Domenico & B. Spitzer & N. Bouvier & J. E. Arango-Ossa & D. Glodzik & J. S. Medina-Martínez & U. Bhanot & J. Gutiérrez-Abril & Y. Zhou & E. Fiala & E. Stockfi, 2022. "Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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