Abstract
Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of “evolutionary herding” approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.
Highlights
Multiple myeloma (MM) is caused by the expansion of clonal plasma cells in the bone marrow[1]
whole-genome sequencing (WGS) resulted in a median of 38× coverage for normal samples (30–44×), 111× for primary tumours (82–155×), and 114× for the 24 relapsed tumours (102–154×) (Supplementary Table 2). 6 of the 80 patients have been the subject of a previous whole-exome sequencing (WES) project[4]
Mutational events in primary tumours We began by surveying for important genetic alterations in the 80 primary MM tumours by considering the contribution of both protein-coding and noncoding Single nucleotide variants (SNVs) and indels, as well as CNAs
Summary
Multiple myeloma (MM) is caused by the expansion of clonal plasma cells in the bone marrow[1]. Our limited knowledge of the molecular changes associated with relapse is a barrier to developing new therapeutic strategies to overcome drug resistance. To advance our understanding of the evolution of MM tumours and the mutational mechanisms that shape their history, we performed whole-genome sequencing (WGS) of 80 newly diagnosed MM tumour-normal pairs, 24 had matched relapsed tumours[2]. WGS allowed us to examine the impact of noncoding mutations, complex structural rearrangements, and telomere structure on MM tumourigenesis analyses not possible in previous studies, which have been based on whole-exome sequencing (WES)[3,4]. Integrating information from multiple types of genomic alterations has allowed us to infer the order of mutational events, and show that relapse is associated with acquisition of new mutations and clonal selection
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