Post-Doctoral Associate University of Miami Miami, Florida, United States
Introduction: APOBEC mutational signatures are among the most important mutational signatures present in the majority of patients with newly diagnosed multiple myeloma (NDMM). APOBEC mutational signatures are primarily caused by two enzymes, APOBEC3A (A3A) and APOBEC3B (A3B). While these genes are expressed in most myeloma cells, their influence on APOBEC mutagenesis appear to be extremely heterogeneous, with some patients having no detectable mutations and others having high contribution (hyper-APOBEC).
Methods: To decipher the mechanism of APOBEC mutagenesis, we utilized 752 whole genomes from NDMM patients enrolled in the CoMMpass study. 723 and 767 had available whole exome sequencing (WES) and RNA sequencing (RNA-Seq) data, respectively.
Results: APOBEC activity was identified in 416/723 (57.5%) patients using WES. Of these, 41 (5.8%) had MAF/MAFB translocations. Overall, 48/723 (6.6%) patients were defined as hyper-APOBEC (13 without MAF/MAFB events).
We used differential expression (DE) analysis between three groups: hyper-APOBEC with MAF/MAFB (HA_TRA: n=31), hyper-APOBEC without MAF/MAFB (HA_NORM: n=8), and non-hyper-APOBEC without MAF/MAFB (WT: n=510). We identified 534 APOBEC-associated genes which were independent from the MAF/MAFB events. Importantly, A3B was higher in hyper-APOBEC with and without MAF/MAFB, while A3A was mostly expressed in MAF/MAFB samples. Using Spearman’s correlation, we identified 50 significantly correlated genes (rho-squared>0.18; p< 0.00001) with A3B. Most of the genes belonged to the APOBEC-associated group defined by the DE and showed cell cycle/proliferation activity, suggesting a link between highly proliferative disease and hyper-APOBEC. To validate this finding, we evaluated the link between these genes and hyper-APOBEC among ICGC breast cancers. Overall, 35 of these genes showed similar correlation in hyper-APOBEC breast. Interestingly, most of these genes appear to be negatively controlled by E2F4, and positively controlled by FOXM1 and MYBL2. These three transcription factors are well-established regulators of the DREAM complex, which has been shown to play a key role in APOBEC transcriptional regulation (Roelofs et al., eLife, 2020).
Next, we compared 131 genomic events to identify potential differences between the hyper-APOBEC and WT. HA_TRA and HA_NORM showed similarities, including a highly complex genomic profile enriched for 1q gain, 13q and 16q deletions (p < 0.05). In terms of gene expression, both groups showed enrichment for GEP70 positivity. Finally, HA_TRA and HA_NORM showed similar poor outcomes compared to WT.
Conclusions: Patients with hyper-APOBEC NDMM are characterized by a distinct transcriptional profile with high cell proliferation, reduced inhibition by the DREAM complex, and a high level of genomic complexity reflected in poorer clinical outcomes.
