Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities

• Published in: Nature communications Vol. 12; no. 1; p. 1861
• Main Authors: Oben, Bénedith, Froyen, Guy, Maclachlan, Kylee H., Leongamornlert, Daniel, Abascal, Federico, Zheng-Lin, Binbin, Yellapantula, Venkata, Derkach, Andriy, Geerdens, Ellen, Diamond, Benjamin T., Arijs, Ingrid, Maes, Brigitte, Vanhees, Kimberly, Hultcrantz, Malin, Manasanch, Elisabet E., Kazandjian, Dickran, Lesokhin, Alexander, Dogan, Ahmet, Zhang, Yanming, Mikulasova, Aneta, Walker, Brian, Morgan, Gareth, Campbell, Peter J., Landgren, Ola, Rummens, Jean-Luc, Bolli, Niccolò, Maura, Francesco
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-03-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 631/67/1990/804; 631/67/69; 692/53/2423; Aneuploidy; Benign monoclonal gammopathy; Disease Progression; DNA Copy Number Variations - genetics; Gene sequencing; Genome, Human - genetics; Genomes; Genomics; Humanities and Social Sciences; Humans; Monoclonal Gammopathy of Undetermined Significance - genetics; Monoclonal Gammopathy of Undetermined Significance - pathology; multidisciplinary; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Mutation; Nucleotide sequence; Polymorphism, Single Nucleotide - genetics; Precursors; Risk Factors; Science; Science (multidisciplinary); Smoldering; Smoldering Multiple Myeloma - genetics; Smoldering Multiple Myeloma - pathology; Whole Genome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22140-0

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (
n
 = 15) are characterized by later initiation in the patient’s life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.
The factors that are associated with myeloma precursor condition progression are not well understood. Here the authors find that monoclonal gammopathies of undetermined significance and smoldering myelomas that did not progress to multiple myelomas have a distinct genomic profile and emerge later in the patient’s life.