IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms9866.html
   My bibliography  Save this article

Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution

Author

Listed:
  • S. Kasar

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School)

  • J. Kim

    (Cancer Program, Broad Institute of Harvard and MIT)

  • R. Improgo

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School)

  • G. Tiao

    (Cancer Program, Broad Institute of Harvard and MIT)

  • P. Polak

    (Cancer Program, Broad Institute of Harvard and MIT)

  • N. Haradhvala

    (Cancer Program, Broad Institute of Harvard and MIT)

  • M. S. Lawrence

    (Cancer Program, Broad Institute of Harvard and MIT)

  • A. Kiezun

    (Cancer Program, Broad Institute of Harvard and MIT)

  • S. M. Fernandes

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School)

  • S. Bahl

    (Cancer Program, Broad Institute of Harvard and MIT)

  • C. Sougnez

    (Cancer Program, Broad Institute of Harvard and MIT)

  • S. Gabriel

    (Cancer Program, Broad Institute of Harvard and MIT)

  • E. S. Lander

    (Cancer Program, Broad Institute of Harvard and MIT)

  • H. T. Kim

    (Dana-Farber Cancer Institute)

  • G. Getz

    (Cancer Program, Broad Institute of Harvard and MIT
    Massachusetts General Hospital
    Harvard Medical School)

  • J. R. Brown

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School)

Abstract

Patients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To better understand their genomic landscape, here we perform whole-genome sequencing on a cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and unmutated IGHV. The most commonly mutated gene in our cohort, IGLL5, shows a mutational pattern suggestive of activation-induced cytidine deaminase (AID) activity. Unsupervised analysis of mutational signatures demonstrates the activities of canonical AID (c-AID), leading to clustered mutations near active transcriptional start sites; non-canonical AID (nc-AID), leading to genome-wide non-clustered mutations, and an ageing signature responsible for most mutations. Using mutation clonality to infer time of onset, we find that while ageing and c-AID activities are ongoing, nc-AID-associated mutations likely occur earlier in tumour evolution.

Suggested Citation

  • S. Kasar & J. Kim & R. Improgo & G. Tiao & P. Polak & N. Haradhvala & M. S. Lawrence & A. Kiezun & S. M. Fernandes & S. Bahl & C. Sougnez & S. Gabriel & E. S. Lander & H. T. Kim & G. Getz & J. R. Brow, 2015. "Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9866
    DOI: 10.1038/ncomms9866
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms9866
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms9866?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Ryan N. Ptashkin & Mark D. Ewalt & Gowtham Jayakumaran & Iwona Kiecka & Anita S. Bowman & JinJuan Yao & Jacklyn Casanova & Yun-Te David Lin & Kseniya Petrova-Drus & Abhinita S. Mohanty & Ruben Bacares, 2023. "Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Luan Nguyen & Arne Hoeck & Edwin Cuppen, 2022. "Machine learning-based tissue of origin classification for cancer of unknown primary diagnostics using genome-wide mutation features," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9866. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.