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Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis

Author

Listed:
  • Teng Gao

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Ryan Ptashkin

    (Memorial Sloan Kettering Cancer Center)

  • Kelly L. Bolton

    (Memorial Sloan Kettering Cancer Center)

  • Maria Sirenko

    (Memorial Sloan Kettering Cancer Center)

  • Christopher Fong

    (Memorial Sloan Kettering Cancer Center)

  • Barbara Spitzer

    (Memorial Sloan Kettering Cancer Center)

  • Kamal Menghrajani

    (Memorial Sloan Kettering Cancer Center)

  • Juan E. Arango Ossa

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Yangyu Zhou

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Elsa Bernard

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Max Levine

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Juan S. Medina Martinez

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Yanming Zhang

    (Memorial Sloan Kettering Cancer Center)

  • Sebastià Franch-Expósito

    (Memorial Sloan Kettering Cancer Center)

  • Minal Patel

    (Memorial Sloan Kettering Cancer Center)

  • Lior Z. Braunstein

    (Memorial Sloan Kettering Cancer Center)

  • Daniel Kelly

    (Memorial Sloan Kettering Cancer Center)

  • Mariko Yabe

    (Memorial Sloan Kettering Cancer Center)

  • Ryma Benayed

    (Memorial Sloan Kettering Cancer Center)

  • Nicole M. Caltabellotta

    (Memorial Sloan Kettering Cancer Center)

  • John Philip

    (Memorial Sloan Kettering Cancer Center)

  • Ederlinda Paraiso

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Simon Mantha

    (Memorial Sloan Kettering Cancer Center)

  • David B. Solit

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Luis A. Diaz

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Michael F. Berger

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Virginia Klimek

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

  • Ross L. Levine

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Ahmet Zehir

    (Memorial Sloan Kettering Cancer Center)

  • Sean M. Devlin

    (Memorial Sloan Kettering Cancer Center)

  • Elli Papaemmanuil

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

Abstract

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7–22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6–33, P

Suggested Citation

  • Teng Gao & Ryan Ptashkin & Kelly L. Bolton & Maria Sirenko & Christopher Fong & Barbara Spitzer & Kamal Menghrajani & Juan E. Arango Ossa & Yangyu Zhou & Elsa Bernard & Max Levine & Juan S. Medina Mar, 2021. "Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20565-7
    DOI: 10.1038/s41467-020-20565-7
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    Cited by:

    1. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Derek W. Brown & Liam D. Cato & Yajie Zhao & Satish K. Nandakumar & Erik L. Bao & Eugene J. Gardner & Aubrey K. Hubbard & Alexander DePaulis & Thomas Rehling & Lei Song & Kai Yu & Stephen J. Chanock &, 2023. "Shared and distinct genetic etiologies for different types of clonal hematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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