title: APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma.
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.
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Brian A
authors.identifier: 0000000286156254
authors.initials: BA
authors.lastname: Walker
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Murison
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Boyle
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Dil B
authors.initials: DB
authors.lastname: Begum
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Nasrin M
authors.initials: NM
authors.lastname: Dahir
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Paula Z
authors.initials: PZ
authors.lastname: Proszek
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melchor
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pawlyn
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kaiser
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: David C
authors.identifier: 0000000308873343
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Ya-Wei
authors.initials: YW
authors.lastname: Qiang
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Jones
authors.affiliation: Clinical Trials Research Unit, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Cairns
authors.affiliation: Clinical Trials Research Unit, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Gregory
authors.affiliation: St James's University Hospital, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Owen
authors.affiliation: St James's University Hospital, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
authors.affiliation: Clinical Immunology, School of Immunity &Infection, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.affiliation: Department of Haematology, Newcastle University, Newcastle-Upon-Tyne NE1 7RU, UK.
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.affiliation: 1] Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK [2] Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.affiliation: 1] Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK [2] Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003564:Cytidine Deaminase / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051258:MafB Transcription Factor / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009101:Multiple Myeloma / Q000235:genetics*; D009154:Mutation; D011379:Prognosis; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: C495607:MAF protein, human; C490407:MAFB protein, human; D051258:MafB Transcription Factor; D015778:Minor Histocompatibility Antigens; D051257:Proto-Oncogene Proteins c-maf; D016271:Proto-Oncogene Proteins c-myc; C495794:APOBEC3B protein, human; C510823:APOBEC4 protein, human; D003564:Cytidine Deaminase