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Revealing the impact of structural variants in multiple myeloma

Rustad, Even H., Yellapantula, Venkata D., Glodzik, Dominik, Maclachlan, Kylee H., Diamond, Benjamin, Boyle, Eileen M., Ashby, Cody, Blaney, Patrick, Gundem, Gunes, Hultcrantz, Malin, Leongamornlert, Daniel, Angelopoulos, Nicos, Agnelli, Luca, Auclair, Daniel, Zhang, Yanming, Dogan, Ahmet, Bolli, Niccolo, Papaemmanuil, Elli, Anderson, Kenneth C., Moreau, Philippe, Avet-Loiseau, Herve, Munshi, Nikhil C., Keats, Jonathan J., Campbell, Peter J., Morgan, Gareth J., Landgren, Ola and Maura, Francesco 2020. Revealing the impact of structural variants in multiple myeloma. Blood Cancer Discovery 1 (3) , pp. 258-273. 10.1158/2643-3230.BCD-20-0132

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The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients 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), SLAMF 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
ISSN: 2643-3230
Funders: EU-ERDF/Welsh Government
Date of Acceptance: 10 September 2020
Last Modified: 09 Feb 2021 15:00

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