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Cited by 165Multiple Myeloma Research and TreatmentsCancer Genomics and DiagnosticsAcute Myeloid Leukemia Research

Timing the Initiation of Multiple Myeloma

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Rustad, Even H., Yellapantula, Venkata, Leongamornlert, Daniel, Bolli, Niccolò, Ledergor, Guy, Nadeu, Ferran, Angelopoulos, Nicos, Dawson, Kevin J. +18 more·2020·Nature Communications
DOI 10.1038/s41467-020-15740-9PMC PMC7174344
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Abstract

The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2 nd-3 rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.

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  • Different patients might experience different exposure in time and intensity in the germinal center, potentially reflecting unique interaction with the external environment.

    “Importantly, based on the different number of GC mutations observed across hundreds of WGS, it has been shown that different patients might experience different exposure in time and intensity, potentially reflecting unique interaction with the external environment.12,13,15,72,73”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [12]

    The Results section (“Temporal patterns of MM mutational signatures”; page unavailable) describes patient-to-patient differences in the timing and contribution of AID mutagenesis, including evidence of continued germinal-center exposure in some patients. The Discussion suggests a prolonged antigen-responsive phase, but does not specifically link those differences to each patient’s unique interaction with the external environment. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Virtually all documented HY cases exhibit clear germinal-center mutagenesis acquired before the duplication, which excludes a pre-germinal-center origin.

    “Virtually all HY cases documented so far exhibit clear GC mutagenesis acquired before the duplication, which excludes a pre-GC origin.9,12,13,69”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [12]

    The Results section on temporal patterns of mutational signatures reports that GC-associated nc-AID mutations were significantly enriched before chromosomal gains in 33 patients, supporting GC mutagenesis before duplication. It does not establish that virtually all documented hyperdiploid (HY) cases show this pattern or that a pre-GC origin is excluded. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • A significant fraction of SMM has already transformed into MM.

    “This temporal similarity between progressive SMM and MM further strengthens the hypothesis that a significant fraction of SMM has already transformed into MM.”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [12]

    The Results section, “Clock-like mutational process in MM” (page unavailable), reports that the estimated SBS5 mutation rate was independent of disease stage, including SMM and newly diagnosed MM. That supports a temporal similarity, but the paper does not establish that a significant fraction of SMM has already transformed into MM or distinguish progressive SMM for this finding. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • SMM that progresses to multiple myeloma has a time of initiation of approximately 30 to 40 years.

    “This has been recently supported by several papers, where using molecular mathematical modeling, it has been shown that SMM that progresses to MM has a time of initiation of approximately 30 to 40 years.9,10,12,13,1515”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [12]

    The Results (‘Timing the initiation and evolution of MM’; page not available) estimate that the first chromosomal duplication occurred an average of 37.5 years before sample collection, supporting the approximate interval. The Methods (‘Subject details’; page not available) include SMM samples, but the 37.5-year estimate is not reported specifically for SMM that progressed to MM; it also dates a chromosomal event rather than the clinical onset of SMM. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • All cases of multiple myeloma are preceded by precursor conditions such as smoldering multiple myeloma and monoclonal gammopathy of undetermined significance, often decades before diagnosis.

    “MM is well-described to be universally preceded by precursor states, often decades before it is even diagnosed.”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [12]

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Cites

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Authors
Rustad, E. H., Yellapantula, V., Leongamornlert, D., Bolli, N., Ledergor, G., Nadeu, F., Angelopoulos, N., Dawson, K. J., Mitchell, T. J., Osborne, R. J., Ziccheddu, B., Carniti, C., Montefusco, V., Corradini, P., Anderson, K. C., Moreau, P., Papaemmanuil, E., Alexandrov, L. B., Puente, X. S., Campo, E., Siebert, R., Avet-Loiseau, H., Landgren, O., Munshi, N., Campbell, P. J., & Maura, F.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Wellcome Sanger Institute (GB)
  • University of Milan (IT)
  • University of California, San Francisco (US)
  • Centro de Investigación Biomédica en Red de Cáncer (ES)
  • Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
  • Harvard University (US)
  • Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR)
  • University of California San Diego (US)
  • Universität Ulm (DE)
Corresponding author
Maura, Francesco
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-04-21
Volume
11
Issue
1
Pages
1917-1917
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-15740-9
PMC
PMC7174344
OpenAlex
W2978474447
Cited by
165
References
8
Citations by year
2026: 15 · 2025: 24 · 2024: 24 · 2023: 29 · 2022: 24 · 2021: 26 · 2020: 19 · 2019: 3
FWCI
12.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • SSRN Electronic Journal (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Open Access at Essex (University of Essex) (acceptedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
  • HAL (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30 CA008748)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
multiple myeloma, tumor evolution, mutational signatures, melphalan, APOBEC mutagenesis, germinal center B cells, clonal evolution, early detection
MeSH terms
APOBEC-1 Deaminase, AICDA (Activation-Induced Cytidine Deaminase), Cytidine Deaminase, DNA Mutational Analysis, Genetics, Humans, Multiple Myeloma, Mutation, Proteins, RNA, Messenger, Minor Histocompatibility Antigens, Gene Expression Regulation, Neoplastic, Linear Models, RNA Editing, Germinal Center, Early Detection of Cancer, Single-Cell Analysis, Exome

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