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APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma

Author

Listed:
  • Brian A. Walker

    (The Institute of Cancer Research)

  • Christopher P. Wardell

    (The Institute of Cancer Research)

  • Alex Murison

    (The Institute of Cancer Research)

  • Eileen M. Boyle

    (The Institute of Cancer Research)

  • Dil B. Begum

    (The Institute of Cancer Research)

  • Nasrin M. Dahir

    (The Institute of Cancer Research)

  • Paula Z. Proszek

    (The Institute of Cancer Research)

  • Lorenzo Melchor

    (The Institute of Cancer Research)

  • Charlotte Pawlyn

    (The Institute of Cancer Research)

  • Martin F. Kaiser

    (The Institute of Cancer Research)

  • David C. Johnson

    (The Institute of Cancer Research)

  • Ya-Wei Qiang

    (Myeloma Institute, University of Arkansas for Medical Sciences)

  • John R. Jones

    (The Institute of Cancer Research)

  • David A. Cairns

    (Clinical Trials Research Unit, University of Leeds)

  • Walter M. Gregory

    (Clinical Trials Research Unit, University of Leeds)

  • Roger G. Owen

    (St James’s University Hospital, University of Leeds)

  • Gordon Cook

    (St James’s University Hospital, University of Leeds)

  • Mark T. Drayson

    (Clinical Immunology, School of Immunity & Infection, University of Birmingham)

  • Graham H. Jackson

    (Newcastle University)

  • Faith E. Davies

    (The Institute of Cancer Research
    Myeloma Institute, University of Arkansas for Medical Sciences)

  • Gareth J. Morgan

    (The Institute of Cancer Research
    Myeloma Institute, University of Arkansas for Medical Sciences)

Abstract

We have sequenced 463 presenting cases of myeloma entered into the UK Myeloma XI study using whole exome sequencing. Here we identify mutations induced as a consequence of misdirected AID in the partner oncogenes of IGH translocations, which are activating and associated with impaired clinical outcome. An APOBEC mutational signature is seen in 3.8% of cases and is linked to the translocation-mediated deregulation of MAF and MAFB, a known poor prognostic factor. Patients with this signature have an increased mutational load and a poor prognosis. Loss of MAF or MAFB expression results in decreased APOBEC3B and APOBEC4 expression, indicating a transcriptional control mechanism. Kataegis, a further mutational pattern associated with APOBEC deregulation, is seen at the sites of the MYC translocation. The APOBEC mutational signature seen in myeloma is, therefore, associated with poor prognosis primary and secondary translocations and the molecular mechanisms involved in generating them.

Suggested Citation

  • Brian A. Walker & Christopher P. Wardell & Alex Murison & Eileen M. Boyle & Dil B. Begum & Nasrin M. Dahir & Paula Z. Proszek & Lorenzo Melchor & Charlotte Pawlyn & Martin F. Kaiser & David C. Johnson, 2015. "APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7997
    DOI: 10.1038/ncomms7997
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    Cited by:

    1. Josh N. Vo & Yi-Mi Wu & Jeanmarie Mishler & Sarah Hall & Rahul Mannan & Lisha Wang & Yu Ning & Jin Zhou & Alexander C. Hopkins & James C. Estill & Wallace K. B. Chan & Jennifer Yesil & Xuhong Cao & Ar, 2022. "The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Atanu Maiti & Adam K. Hedger & Wazo Myint & Vanivilasini Balachandran & Jonathan K. Watts & Celia A. Schiffer & Hiroshi Matsuo, 2022. "Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Mark Bustoros & Shankara Anand & Romanos Sklavenitis-Pistofidis & Robert Redd & Eileen M. Boyle & Benny Zhitomirsky & Andrew J. Dunford & Yu-Tzu Tai & Selina J. Chavda & Cody Boehner & Carl Jannes Neu, 2022. "Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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