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

TY - JOUR

T1 - The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma

AU - Cirrincione, Anthony M

AU - Poos, Alexandra M

AU - Ziccheddu, Bachisio

AU - Kaddoura, Marcella

AU - Baertsch, Marc-Andrea

AU - Maclachlan, Kylee H

AU - Chojnacka, Monika

AU - Diamond, Benjamin T

AU - John, Lukas

AU - Reichert, Philipp

AU - Huhn, Stefanie

AU - Blaney, Patrick

AU - Gagler, Dylan C

AU - Rippe, Karsten

AU - Zhang, Yanming

AU - Dogan, Ahmet

AU - Lesokhin, Alexander M

AU - Davies, Faith E

AU - Goldschmidt, Hartmut

AU - Fenk, Roland

AU - Weisel, Katja C

AU - Mai, Elias K

AU - Korde, Neha

AU - Morgan, Gareth J

AU - Usmani, Saad Z

AU - Landgren, Ola

AU - Raab, Marc S

AU - Weinhold, Niels

AU - Maura, Francesco

N1 - Copyright © 2024 American Society of Hematology.

PY - 2024/8/15

Y1 - 2024/8/15

N2 - 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.

AB - 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.

U2 - 10.1182/blood.2024024299

DO - 10.1182/blood.2024024299

M3 - SCORING: Journal article

C2 - 38728430

VL - 144

SP - 771

EP - 783

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 7

ER -