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Heterogeneity of genomic evolution and mutational profiles in multiple myeloma
Open accessAbstract
Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment. Multiple myeloma is a malignant plasma cell disorder with a complex molecular pathogenesis. Here, the authors perform whole-exome sequencing, copy-number profiling and cytogenetic analysis in 84 myeloma samples and highlight the diversity and evolution of the mutational profile underlying the disease.
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Metadata
- Authors
- Bolli, N., Avet-Loiseau, H., Wedge, D. C., Van Loo, P., Alexandrov, L. B., Martincorena, I., Dawson, K. J., Iorio, F., Nik-Zainal, S., Bignell, G. R., Hinton, J. W., Li, Y., Tubio, J. M. C., McLaren, S., O' Meara, S., Butler, A. P., Teague, J. W., Mudie, L., Anderson, E., Rashid, N., Tai, Y.-T., Shammas, M. A., Sperling, A. S., Fulciniti, M., Richardson, P. G., Parmigiani, G., Magrangeas, F., Minvielle, S., Moreau, P., Attal, M., Facon, T., Futreal, P. A., Anderson, K. C., Campbell, P. J., & Munshi, N. C.
- Affiliations
- Wellcome Sanger Institute (GB)
- European Bioinformatics Institute (GB)
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier Universitaire de Nantes (FR)
- Inserm (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- University of Cambridge (GB)
- Corresponding author
- Campbell, Peter J.
- Munshi, Nikhil C.
- ORCID
- Wedge, David C.
- Alexandrov, Ludmil B.
- Iorio, Francesco
- Hinton, Jonathan W.
- Li, Yilong
- McLaren, Stuart
- Teague, Jon W.
- Anderson, Elizabeth
- Rashid, Naim
- Tai, Yu-Tzu
- Shammas, Masood A.
- Sperling, Adam S.
- Fulciniti, Mariateresa
- Richardson, Paul G.
- Parmigiani, Giovanni
- Magrangeas, Florence
- Moreau, Philippe
- Attal, Michel
- Facon, Thierry
- Futreal, P Andrew
- Anderson, Kenneth C.
- Campbell, Peter J.
- Munshi, Nikhil C.
- Venue
- Nature Communications
- Published
- 2014-01-16
- Volume
- 5
- Issue
- 1
- Pages
- 2997-2997
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3905727
- OpenAlex
- W2104195581
- Cited by
- 875
- References
- 62
- Citations by year
- 2026: 26 · 2025: 37 · 2024: 56 · 2023: 50 · 2022: 91 · 2021: 87 · 2020: 92 · 2019: 75 · 2018: 90 · 2017: 90 · 2016: 71 · 2015: 65 · 2014: 43
- FWCI
- 63.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Research Explorer (The University of Manchester) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Apollo
- Funders
- U.S. Department of Veterans Affairs (I01 BX001584)
- Wellcome Trust (077012/Z/05/Z, 077012, 088340, 100007)
- Lady Tata Memorial Trust
- Agence Nationale de la Recherche (ANR-11-PHUC-0001)
- Vlaamse regering
- National Institutes of Health (P50-100007, PO1-155258, 5p01ca078378-15, RO1-124929, PO1-78378)
- U.S. Public Health Service (P0-1 155258, RCA125711C, P50-100007, P0178378, R01-124929)
- National Cancer Institute (R01CA125711, P01-CA078378, P50CA100707, T32CA106209, P01CA155258)
- 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, clonal evolution, subclonal heterogeneity, mutation spectrum, kataegis, somatic hypermutation, copy number alterations, plasma cell malignancy, lateral-torsional buckling, ROBO1, EGR1
- MeSH terms
- Roundabout Proteins, Adult, Aged, Humans, Membrane Proteins, Middle Aged, Multiple Myeloma, Mutation, Nerve Tissue Proteins, Proto-Oncogene Proteins, Receptors, Immunologic, Transcription Factors, Cohort Studies, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Sequence Analysis, DNA, ras Proteins, Genetic Heterogeneity, Evolution, Molecular, Mutation, Missense, GTP Phosphohydrolases, Antigens, Nuclear, Proto-Oncogene Proteins B-raf, Early Growth Response Protein 1, Lymphotoxin-beta, DNA Copy Number Variations, Exome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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