EGAGenomicsGareth Morganhttps://ega-archive.org/dacs/EGAC00001000307EGAEGA DAC EGAC00001000307EGAGareth.Morgan@nyulangone.orgWe 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.APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma.Walker Brian A BA, Wardell Christopher P CP, Murison Alex A, Boyle Eileen M EM, Begum Dil B DB, Dahir Nasrin M NM, Proszek Paula Z PZ, Melchor Lorenzo L, Pawlyn Charlotte C, Kaiser Martin F MF, Johnson David C DC, Qiang Ya-Wei YW, Jones John R JR, Cairns David A DA, Gregory Walter M WM, Owen Roger G RG, Cook Gordon G, Drayson Mark T MT, Jackson Graham H GH, Davies Faith E FE, Morgan Gareth J GJfalseThis DAC is to control access to data contained within dataset EGAS00001001147, for Myeloma XI clinical trial patients.Data Access Committee EGAC00001000307EGAC00001000307960625904160EGAS00001001147EGAD00001001358