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.

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

“…About two-thirds of patients who are newly diagnosed with MM harbor MYC activation, which correlates with adverse clinical outcome (3). In about 20 to 40% of the patients, this is explained by translocations that involve the MYC locus (4, 5). Another 10% of patients harbor a gain of 8q24 comprising MYC (6).…”

Crystal Structure of the DNA Deaminase APOBEC3B Catalytic Domain

“…Specifically, the most frequently mutated cytosines in these cancers are in 5Ј-TCA, 5Ј-TCG, and 5Ј-TCT trinucleotide motifs, which resemble the actual biochemical preferences of recombinant A3B (5Ј-TCA ϭ 5Ј-TCG Ͼ 5Ј-TCT) (17,21). Third, high A3B mRNA expression levels correlate with poor outcomes for estrogen receptor-positive breast cancer (24,25), renal cancer (26), and multiple myeloma (27). Fourth, the spectrum of activating mutations in PIK3CA is biased toward a potential A3B deamination hot spot in A3B-high, HPV-infected head/neck tumors, in comparison to A3B-low, virusnegative tumors (20).…”

Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

“…WES libraries were prepared using the SureSelect QXT sample prep kit and the SureSelect Clinical Research Exome kit (Agilent), with additional baits covering the Ig and MYC loci. 13 Paired-end sequencing was performed to an average sequencing depth of 1183 on a HiSeq2500 (Illumina). High-resolution HumanOmni 2.5 SNP array (Illumina) data were available for 30 of 33 patients.…”

“…Recently, an enrichment of C.G and C.T mutations in the context of TpCpA and TpCpT was found in cases with translocations involving MAF or MAFB that are associated with deregulated activity of APOBECs. 13 These enzymes are involved in somatic hypermutation during antibody affinity maturation and, when abnormally expressed, may cause collateral genomic damage. 27 Our data set contained 8 MF cases, which were characterized by upregulation of MAF or MAFB.…”