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The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients

Author

Listed:
  • Francesc Muyas

    (European Bioinformatics Institute, Hinxton)

  • Manuel José Gómez Rodriguez

    (Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC))

  • Rita Cascão

    (Universidade de Lisboa)

  • Angela Afonso

    (Universidade de Lisboa)

  • Carolin M. Sauer

    (European Bioinformatics Institute, Hinxton)

  • Claudia C. Faria

    (Universidade de Lisboa
    Centro Hospitalar Universitário Lisboa Norte (CHULN))

  • Isidro Cortés-Ciriano

    (European Bioinformatics Institute, Hinxton)

  • Ignacio Flores

    (Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
    CSIC-UAM, Cantoblanco)

Abstract

Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44287-8
    DOI: 10.1038/s41467-023-44287-8
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    as
    1. Ofer Shoshani & Simon F. Brunner & Rona Yaeger & Peter Ly & Yael Nechemia-Arbely & Dong Hyun Kim & Rongxin Fang & Guillaume A. Castillon & Miao Yu & Julia S. Z. Li & Ying Sun & Mark H. Ellisman & Bing, 2021. "Chromothripsis drives the evolution of gene amplification in cancer," Nature, Nature, vol. 591(7848), pages 137-141, March.
    2. Viktor A. Adalsteinsson & Gavin Ha & Samuel S. Freeman & Atish D. Choudhury & Daniel G. Stover & Heather A. Parsons & Gregory Gydush & Sarah C. Reed & Denisse Rotem & Justin Rhoades & Denis Loginov & , 2017. "Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    3. Niek van Wietmarschen & Sriram Sridharan & William J. Nathan & Anthony Tubbs & Edmond M. Chan & Elsa Callen & Wei Wu & Frida Belinky & Veenu Tripathi & Nancy Wong & Kyla Foster & Javad Noorbakhsh & Ki, 2020. "Repeat expansions confer WRN dependence in microsatellite-unstable cancers," Nature, Nature, vol. 586(7828), pages 292-298, October.
    4. Mahmoud Ghandi & Franklin W. Huang & Judit Jané-Valbuena & Gregory V. Kryukov & Christopher C. Lo & E. Robert McDonald & Jordi Barretina & Ellen T. Gelfand & Craig M. Bielski & Haoxin Li & Kevin Hu & , 2019. "Next-generation characterization of the Cancer Cell Line Encyclopedia," Nature, Nature, vol. 569(7757), pages 503-508, May.
    5. Sally M. Dewhurst & Xiaotong Yao & Joel Rosiene & Huasong Tian & Julie Behr & Nazario Bosco & Kaori K. Takai & Titia de Lange & Marcin Imieliński, 2021. "Structural variant evolution after telomere crisis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    6. Martin Peifer & Falk Hertwig & Frederik Roels & Daniel Dreidax & Moritz Gartlgruber & Roopika Menon & Andrea Krämer & Justin L. Roncaioli & Frederik Sand & Johannes M. Heuckmann & Fakhera Ikram & Rene, 2015. "Telomerase activation by genomic rearrangements in high-risk neuroblastoma," Nature, Nature, vol. 526(7575), pages 700-704, October.
    7. Yilong Li & Nicola D. Roberts & Jeremiah A. Wala & Ofer Shapira & Steven E. Schumacher & Kiran Kumar & Ekta Khurana & Sebastian Waszak & Jan O. Korbel & James E. Haber & Marcin Imielinski & Joachim We, 2020. "Patterns of somatic structural variation in human cancer genomes," Nature, Nature, vol. 578(7793), pages 112-121, February.
    8. Michal Zalzman & Geppino Falco & Lioudmila V. Sharova & Akira Nishiyama & Marshall Thomas & Sung-Lim Lee & Carole A. Stagg & Hien G. Hoang & Hsih-Te Yang & Fred E. Indig & Robert P. Wersto & Minoru S., 2010. "Zscan4 regulates telomere elongation and genomic stability in ES cells," Nature, Nature, vol. 464(7290), pages 858-863, April.
    9. 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.
    10. Luiza Moore & Alex Cagan & Tim H. H. Coorens & Matthew D. C. Neville & Rashesh Sanghvi & Mathijs A. Sanders & Thomas R. W. Oliver & Daniel Leongamornlert & Peter Ellis & Ayesha Noorani & Thomas J. Mit, 2021. "The mutational landscape of human somatic and germline cells," Nature, Nature, vol. 597(7876), pages 381-386, September.
    11. Ofer Shoshani & Simon F. Brunner & Rona Yaeger & Peter Ly & Yael Nechemia-Arbely & Dong Hyun Kim & Rongxin Fang & Guillaume A. Castillon & Miao Yu & Julia S. Z. Li & Ying Sun & Mark H. Ellisman & Bing, 2021. "Publisher Correction: Chromothripsis drives the evolution of gene amplification in cancer," Nature, Nature, vol. 591(7850), pages 19-19, March.
    12. Pavithra Viswanath & Georgios Batsios & Joydeep Mukherjee & Anne Marie Gillespie & Peder E. Z. Larson & H. Artee Luchman & Joanna J. Phillips & Joseph F. Costello & Russell O. Pieper & Sabrina M. Rone, 2021. "Non-invasive assessment of telomere maintenance mechanisms in brain tumors," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    13. Alexandre Nonneville & Roger R. Reddel, 2021. "Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX," Nature Communications, Nature, vol. 12(1), pages 1-4, December.
    14. Pedro A. Mateos-Gomez & Fade Gong & Nidhi Nair & Kyle M. Miller & Eros Lazzerini-Denchi & Agnel Sfeir, 2015. "Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination," Nature, Nature, vol. 518(7538), pages 254-257, February.
    15. Stephen Cristiano & Alessandro Leal & Jillian Phallen & Jacob Fiksel & Vilmos Adleff & Daniel C. Bruhm & Sarah Østrup Jensen & Jamie E. Medina & Carolyn Hruban & James R. White & Doreen N. Palsgrove &, 2019. "Genome-wide cell-free DNA fragmentation in patients with cancer," Nature, Nature, vol. 570(7761), pages 385-389, June.
    16. Rajika Arora & Yongwoo Lee & Harry Wischnewski & Catherine M. Brun & Tobias Schwarz & Claus M. Azzalin, 2014. "RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
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