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Development of hyperdiploidy starts at an early age and takes a decade to complete
Open accessAbstract
Nearly half of patients with multiple myeloma (MM) have hyperdiploidy (HMM) at diagnosis. Although HMM occurs early, the mutational processes before and after hyperdiploidy are still unclear. Here, we used 72 whole-genome sequencing samples from patients with HMM and identified pre- and post-HMM mutations to define the chronology of the development of hyperdiploidy. An MM cell accumulated a median of 0.56 mutations per megabase before HMM, and for every clonal pre-HMM mutation, 1.21 mutations per megabase accumulated after HMM. This analysis using mutations before and after hyperdiploidy shows that hyperdiploidy happens after somatic hypermutation. Prehyperdiploidy mutations are activation-induced cytidine deaminase and age/clock-like signature driven, whereas posthyperdiploidy mutations are from DNA damage and APOBEC. Interestingly, the first hyperdiploidy event occurred within the first 3 decades of life and took a decade to complete. Copy number changes affecting chromosomes 15 and 19 occurred first. Finally, mutations before initiating event affected chromosomes at different rates, whereas post-initiating event mutational processes affect each chromosome equally.
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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 [13]
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 [13]
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 [13]
Initial development of HY occurs at a very early age, in the 2nd and 3rd decade of life, with acquisition of additional trisomies and aneuploidies in subsequent decades.
“Different independent studies have indicated initial development of HY at a very early age, in 2nd and 3rd decade of life with acquisition of additional trisomies and aneuploidies in subsequent decade.9,10,12,13,15”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [13]
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 [13]
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 [13]
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Evolution of Multiple Myeloma from a Genomic Perspective
Maura, F., Samur, M., & Munshi, N. (2026) · Blood · doi:10.1182/blood.2024026313 · Cited by 8
Self-citation
Metadata
- Authors
- Samur, M. K., Aktas Samur, A., Shah, P., Park, J. S., Fulciniti, M., Shammas, M., Corre, J., Anderson, K. C., Parmigiani, G., Avet-Loiseau, H., & Munshi, N. C.
- Affiliations
- Harvard University (US)
- 3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
- Dartmouth–Hitchcock Medical Center (US)
- Institut universitaire du cancer de Toulouse Oncopole (FR)
- 5Unité de Genomique du Myélome, University Cancer Center of Toulouse Institut National de la Santé, Toulouse, France
- Corresponding author
- Munshi, Nikhil C.
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2025-01-30
- Volume
- 145
- Issue
- 5
- Pages
- 520-525
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC12782975
- OpenAlex
- W4404582846
- Cited by
- 13
- References
- 0
- Citations by year
- 2026: 3 · 2025: 10
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- HAL (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001584)
- National Cancer Institute (P50CA100707, 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
- hyperdiploidy, multiple myeloma, somatic hypermutation, mutation accumulation, clonal evolution, APOBEC mutagenesis, DNA damage, activation-induced cytidine deaminase, copy number alterations, chromosome 15, chromosome 19, mutational processes
- MeSH terms
- Whole Genome Sequencing, Adult, Age Factors, Aged, Cytidine Deaminase, Diploidy, Female, Humans, Male, Middle Aged, Multiple Myeloma, Mutation
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