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Cited by 278Multiple Myeloma Research and TreatmentsCancer Genomics and DiagnosticsAcute Myeloid Leukemia Research

Genomic landscape and chronological reconstruction of driver events in multiple myeloma

Open access
Maura, Francesco, Bolli, Niccoló, Angelopoulos, Nicos, Dawson, Kevin J., Leongamornlert, Daniel, Martincorena, Inigo, Mitchell, Thomas J., Fullam, Anthony +20 more·2019·Nature Communications
DOI 10.1038/s41467-019-11680-1PMC PMC6707220

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Abstract

The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Here we report a catalog and hierarchy of driver lesions using sequences from 67 MM genomes serially collected from 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups with distinct sets of co-operating events. Focusing on whole genome sequencing data, complex structural events emerge as major drivers, including chromothripsis and a novel replication-based mechanism of templated insertions, which typically occur early. Hyperdiploidy also occurs early, with individual trisomies often acquired in different chronological windows during evolution, and with a preferred order of acquisition. Conversely, positively selected point mutations, whole genome duplication and chromoplexy events occur in later disease phases. Thus, initiating driver events, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of evolution that are biologically relevant but heterogeneous across patients.

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  • The B-cells from which multiple myeloma originates experience prolonged or chronic stimulation in the germinal center.

    “In fact, several studies have supported the idea that the B-cells from which MM originate, experience a prolonged/chronic stimulation in the GC.15,40,41,70,71”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [71]

    The Introduction describes early genetic drivers of multiple myeloma, and the Discussion describes its evolutionary trajectory, but neither addresses prolonged or chronic stimulation of its precursor B cells in the germinal center. Searches for germinal-center stimulation, antigen exposure, and somatic hypermutation found no passage establishing that claim in our copy. (LLM, conf=0.72)

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Cited by

Sorted by citations

Authors
Maura, F., Bolli, N., Angelopoulos, N., Dawson, K. J., Leongamornlert, D., Martincorena, I., Mitchell, T. J., Fullam, A., Gonzalez, S., Szalat, R., Abascal, F., Rodriguez-Martin, B., Samur, M. K., Glodzik, D., Roncador, M., Fulciniti, M., Tai, Y. T., Minvielle, S., Magrangeas, F., Moreau, P., Corradini, P., Anderson, K. C., Tubio, J. M. C., Wedge, D. C., Gerstung, M., Avet-Loiseau, H., Munshi, N., & Campbell, P. J.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • University of Essex (GB)
  • Wellcome Sanger Institute (GB)
  • Harvard University (US)
  • Centre National de la Recherche Scientifique (FR)
  • University of Milan (IT)
  • University of Oxford (GB)
  • European Bioinformatics Institute (GB)
Corresponding author
  • Munshi, Nikhil
  • Campbell, Peter J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-08-23
Volume
10
Issue
1
Pages
3835-3835
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-11680-1
PMC
PMC6707220
OpenAlex
W2969709096
Cited by
278
References
6
Citations by year
2026: 18 · 2025: 27 · 2024: 43 · 2023: 44 · 2022: 38 · 2021: 52 · 2020: 45 · 2019: 8
FWCI
25.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, cc-by)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
  • Open Access at Essex (University of Essex) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Hispana (submittedVersion, cc-by)
  • Repositorio institucional da Universidade de Santiago de Compostela (University of Santiago de Compostela) (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • U.S. Department of Veterans Affairs (I01 BX001584, I01BX001584-01)
  • Memorial Sloan-Kettering Cancer Center (P30 CA008748)
  • Wellcome Trust (103858/Z/14/Z)
  • Cancer Research UK (27176, 21777)
  • European Commission (HORIZON2020)
  • Associazione Italiana per la Ricerca sul Cancro (17658)
  • Associazione Italiana Contro le Leucemie-Linfomi e Mieloma
  • Società Italiana di Ematologia Sperimentale
  • National Institutes of Health (P01-155258, I01BX001584-01, I01-BX001584, CA008748)
  • National Cancer Institute (P30CA, 008748, CA008748, P50CA100707, P01155258, P30CA008748, P01CA155258)
  • H2020 European Research Council (817997)
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, driver mutations, genomic heterogeneity, chromothripsis, hyperdiploidy, trisomy, chromoplexy, whole-genome duplication, point mutations, structural genomic alterations, Bayesian clustering, tumor subtypes, disease progression
MeSH terms
Chromothripsis, Whole Genome Sequencing, Adult, Aged, Bayes Theorem, Bone Marrow, Chromosomes, Human, DNA Replication, Female, Humans, Male, Middle Aged, Models, Genetic, Multiple Myeloma, Phylogeny, Time Factors, Genome, Human, Point Mutation, Genomics, Carcinogenesis

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