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

Nat Commun. 2015 Apr 23;6:6997. doi: 10.1038/ncomms7997.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cytidine Deaminase / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • MafB Transcription Factor / genetics
  • Male
  • Middle Aged
  • Minor Histocompatibility Antigens
  • Multiple Myeloma / genetics*
  • Mutation
  • Prognosis
  • Proto-Oncogene Proteins c-maf / genetics
  • Proto-Oncogene Proteins c-myc / genetics
  • Translocation, Genetic / genetics*

Substances

  • MAF protein, human
  • MAFB protein, human
  • MafB Transcription Factor
  • Minor Histocompatibility Antigens
  • Proto-Oncogene Proteins c-maf
  • Proto-Oncogene Proteins c-myc
  • APOBEC3B protein, human
  • APOBEC4 protein, human
  • Cytidine Deaminase