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The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma

Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating mo...

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Main Authors: Cirrincione, Anthony (Author) , Poos, Alexandra (Author) , Ziccheddu, Bachisio (Author) , Kaddoura, Marcella (Author) , Bärtsch, Marc-Andrea (Author) , Maclachlan, Kylee (Author) , Chojnacka, Monika (Author) , Diamond, Benjamin (Author) , John, Lukas (Author) , Reichert, Philipp (Author) , Huhn, Stefanie (Author) , Blaney, Patrick (Author) , Gagler, Dylan (Author) , Rippe, Karsten (Author) , Zhang, Yanming (Author) , Dogan, Ahmet (Author) , Lesokhin, Alexander M. (Author) , Davies, Faith (Author) , Goldschmidt, Hartmut (Author) , Fenk, Roland (Author) , Weisel, Katja C. (Author) , Mai, Elias K. (Author) , Korde, Neha (Author) , Morgan, Gareth J. (Author) , Usmani, Saad (Author) , Landgren, Ola (Author) , Raab, Marc-Steffen (Author) , Weinhold, Niels (Author) , Maura, Francesco (Author)
Format: Article (Journal)
Language:English
Published: August 15, 2024
In: Blood
Year: 2024, Volume: 144, Issue: 7, Pages: 771-783
ISSN:1528-0020
DOI:10.1182/blood.2024024299
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2024024299
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Author Notes:Anthony M. Cirrincione, Alexandra M. Poos, Bachisio Ziccheddu, Marcella Kaddoura, Marc-Andrea Bärtsch, Kylee Maclachlan, Monika Chojnacka, Benjamin Diamond, Lukas John, Philipp Reichert, Stefanie Huhn, Patrick Blaney, Dylan Gagler, Karsten Rippe, Yanming Zhang, Ahmet Dogan, Alexander M. Lesokhin, Faith Davies, Hartmut Goldschmidt, Roland Fenk, Katja C. Weisel, Elias K. Mai, Neha Korde, Gareth J. Morgan, Saad Usmani, Ola Landgren, Marc S. Raab, Niels Weinhold, Francesco Maura

MARC

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520 |a Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM. 
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