Mutational processes contributing to the development of multiple myeloma

Abstract

To gain insight into multiple myeloma (MM) tumorigenesis, we analyzed the mutational signatures in 874 whole-exome and 850 whole-genome data from the CoMMpass Study. We identified that coding and non-coding regions are differentially dominated by distinct single-nucleotide variant (SNV) mutational signatures, as well as five de novo structural rearrangement signatures. Mutational signatures reflective of different principle mutational processes—aging, defective DNA repair, and apolipoprotein B editing complex (APOBEC)/activation-induced deaminase activity—characterize MM. These mutational signatures show evidence of subgroup specificity—APOBEC-attributed signatures associated with MAF translocation t(14;16) and t(14;20) MM; potentially DNA repair deficiency with t(11;14) and t(4;14); and aging with hyperdiploidy. Mutational signatures beyond that associated with APOBEC are independent of established prognostic markers and appear to have relevance to predicting high-risk MM.

An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics

“…At diagnosis, the major mutational signatures in tumours were those indicative of aging (SBS5), AID/ APOBEC (SBS2, 9, and 13), and flat signatures (SBS5, 8, and 40) as previously observed 7,25 ( Supplementary Figs. 16 and 17).…”

“…Telomere length was estimated using Telomerecat 24 with default parameters. Kataegis foci were identified using the KataegisPortal with default parameters ( https://github.com/MeichunCai/KataegisPortal ), and defined as having six or more consecutive mutations with an average mutational distance ≤1 Kb, excluding immune hypermutated regions 25 .…”

“…We next performed signature fitting using deconstructSigs 42 considering only those COSMIC signatures extracted de novo, as previously recommended 43 . In view of potential ambiguous assignment, we combined the contributions of the flat profile signatures 5, 8, and 40 25,42,43 , excluding signature 3 as this signature is unlikely to be active in MM 43 . As previously advocated, we compared mutational signature proportions in paired primary and relapsed samples using the chi-squared test 13 .…”

Molecular basis of clonal evolution in multiple myeloma

“…Little is known about the mechanisms underlying the acquisition of non-synonymous point mutations in Ras family oncogenes by MM cells; however, the involvement of the APOBEC3B cytidine deaminase was suggested by a recent comprehensive analysis of the mutation signature of multiple cancers [37][38][39] and subsequent biochemical studies [40,41]. APOBEC3B confers hypermutator phenotypes to cancer cells by converting cytidine to uracil/thymidine in TCN trinucleotide repeats in the genome [40][41][42]. This enzyme has been demonstrated to be a transcriptional target of Maf transcription factors and may contribute to rapid progression and treatment resistance of MM cases carrying t (14;16) and t (14;20) [37,42].…”

“…APOBEC3B confers hypermutator phenotypes to cancer cells by converting cytidine to uracil/thymidine in TCN trinucleotide repeats in the genome [40][41][42]. This enzyme has been demonstrated to be a transcriptional target of Maf transcription factors and may contribute to rapid progression and treatment resistance of MM cases carrying t (14;16) and t (14;20) [37,42]. During the progression of MGUS to MM, c-Myc overexpression occurs at 15% frequency exclusively in the latter probably via superenhancermediated hyperactivation of transcription [43].…”