The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma Journal Article
| Authors: | Cirrincione, A. M.; Poos, A. M.; Ziccheddu, B.; Kaddoura, M.; Bärtsch, M. A.; Maclachlan, K.; Chojnacka, M.; Diamond, B.; John, L.; Reichert, P.; Huhn, S.; Blaney, P.; Gagler, D.; Rippe, K.; Zhang, Y.; Dogan, A.; Lesokhin, A. M.; Davies, F.; Goldschmidt, H.; Fenk, R.; Weisel, K. C.; Mai, E. K.; Korde, N.; Morgan, G. J.; Usmani, S.; Landgren, O.; Raab, M. S.; Weinhold, N.; Maura, F. |
| Article Title: | The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma |
| Abstract: | 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. © 2024 American Society of Hematology |
| Keywords: | adult; cancer survival; controlled study; survival analysis; gene translocation; major clinical study; overall survival; single nucleotide polymorphism; gene deletion; genetics; lenalidomide; cancer combination chemotherapy; chromosome 1; chromosome 19; allele; progression free survival; bortezomib; multiple myeloma; gene expression; cohort analysis; gene locus; genetic association; gene frequency; cytogenetics; dexamethasone; protein p53; carcinogenesis; chromosome aberration; oncogene; tumor suppressor gene; germinal center; activation induced cytidine deaminase; immunoglobulin heavy chain; immunoglobulin heavy chains; cyclin dependent kinase inhibitor 1b; nucleotide sequence; chromosome translocation; translocation, genetic; upregulation; gene silencing; heterozygosity loss; immunoglobulin class switching; chromosome aberrations; karyotype; chromosome 18; chromosome 21; human chromosome; chromosome 11; genes, tumor suppressor; carfilzomib; nucleotide; chromosome 3; chromosome 7; dna methyltransferase 3a; chromosome 9; molecular pathology; trisomy; chromosome 10; chromosome 5; clinical outcome; nucleic acid base substitution; transposase; gene expression level; chromosome duplication; chromosome 15; chromosome 14; gain of function mutation; tumor necrosis factor receptor associated factor 3; humans; human; male; female; article; whole genome sequencing; rna sequencing; elotuzumab; max protein; daratumumab; single cell rna seq; large chromosomal gain |
| Journal Title: | Blood |
| Volume: | 144 |
| Issue: | 7 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2024-08-15 |
| Start Page: | 771 |
| End Page: | 783 |
| Language: | English |
| DOI: | 10.1182/blood.2024024299 |
| PUBMED: | 38728430 |
| PROVIDER: | scopus |
| PMCID: | PMC11375460 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF-- Source: Scopus |
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374Lesokhin -
469Dogan -
203Zhang -
155Maclachlan -
327Usmani
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