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

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, Ya-Wei Qiang, John R. Jones, David A. Cairns, Walter M. Gregory, Roger G. Owen, Gordon Cook, Mark T. Drayson, Graham H. Jackson, Faith E. Davies and Gareth J. Morgan ()
Additional contact information
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
Gareth J. Morgan: The Institute of Cancer Research

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7997

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