Revealing the Impact of Structural Variants in Multiple Myeloma

Abstract

The landscape of structural variants (SV) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 patients with multiple myeloma by low-coverage long-insert whole-genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (TNFRSF17), SLAM7, and MCL1. Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as CCND1 and MYC. Importantly, in 31% of patients, two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis. Significance: Previous genomic studies in multiple myeloma have largely focused on single-nucleotide variants, recurrent copy-number alterations, and recurrent translocations. Here, we demonstrate the crucial role of SVs and complex events in the development of multiple myeloma and highlight the importance of whole-genome sequencing to decipher its genomic complexity. See related commentary by Bergsagel and Kuehl, p. 221. This article is highlighted in the In This Issue feature, p. 215

Copy number signatures predict chromothripsis and associate with poor clinical outcomes in patients with newly diagnosed multiple myeloma

“…Genome-wide somatic CN profiles were generated from 752 NDMM patients with low-coverage long-insert WGS (median 4-8x) from the CoMMpass study (NCT01454297; IA13; Supplementary Table 1 ) 14,15 . The final SV catalog was generated by combining the two SV calling algorithms, DELLY 16 and Manta 17 with CN data, followed by a series of quality filters (see Methods ) 9 . According to the most recently published criteria 1-5 , at least one chromothripsis event was observed in 24% of the entire series 9 .…”

“…The final SV catalog was generated by combining the two SV calling algorithms, DELLY 16 and Manta 17 with CN data, followed by a series of quality filters (see Methods ) 9 . According to the most recently published criteria 1-5 , at least one chromothripsis event was observed in 24% of the entire series 9 . Patients with chromothripsis events were characterized by poor clinical outcomes, with chromothripsis being associated with multiple unfavorable clinical and genomic prognostic factors including translocations involving MAF , MAFB and MMSET , increased APOBEC mutational activity, del17p13 and TP53 mutations 9 .…”

“…Given the complex CN features noted in CN-SIG4 and CN-SIG5 ( Figure 2 ), we examined the association of these signatures with known MM genomic features 9,14,19-22 . Both signatures were correlated with features of high-risk MM ( Figure 3a ), including translocations involving MAF / MAFB (p=0.0005), APOBEC mutational activity (i.e.…”

“…Recently, we reported a comprehensive study of structural variation (SV) in a series of 752 newly diagnosed multiple myeloma (NDMM) from the CoMMpass trial for which long-insert low-coverage WGS was available (NCT01454297) 9 . Using the latest criteria for chromothripsis 1-5 and manual curation, we reported a 24% prevalence of chromothripsis, making multiple myeloma (MM) the hematological cancer with the highest documented prevalence of chromothripsis 1,5,10,11 .…”

The Molecular Pathogenesis of Multiple Myeloma

“… 49 , 50 On the contrary, and similar to solid cancers, structural events – many of which are complex and non-recurrent, yet impacting recurrent driver genes – are the events that drive and define the disease. 51 …”