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Cited by 49Multiple Myeloma Research and TreatmentsCancer Genomics and DiagnosticsGenomic variations and chromosomal abnormalities

Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma

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Maclachlan, Kylee H., Rustad, Even H., Derkach, Andriy, Zheng-Lin, Binbin, Yellapantula, Venkata, Diamond, Benjamin, Hultcrantz, Malin, Ziccheddu, Bachisio +9 more·2021·Nature Communications
DOI 10.1038/s41467-021-25469-8PMC PMC8397708

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Abstract

Chromothripsis is detectable in 20–30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study we interrogate 752 NDMM patients using whole genome sequencing (WGS) to investigate the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC = 0.90) and can be used identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis is confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC = 0.97) and an independent series of 34 NDMM (AUC = 0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we are able to predict both the presence of chromothripsis (AUC = 0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.

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  • The underlying mechanisms in multiple myeloma with BRCA inactivation might differ from those seen in solid tumors.

    “The same patterns are not observed in MM with BRCA inactivation via germline or somatic events, suggesting that the underlying mechanisms might differ from what is seen in solid tumors.49,50”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [50]

    The Introduction compares the timing and complexity of chromothripsis in multiple myeloma and solid cancers, but does not make that comparison for cases with BRCA inactivation. A search for BRCA inactivation and BRCAness found no passage addressing whether its underlying mechanisms differ between those cancers. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • The same indel and structural variant patterns are not observed in multiple myeloma with BRCA inactivation via germline or somatic events.

    “The same patterns are not observed in MM with BRCA inactivation via germline or somatic events, suggesting that the underlying mechanisms might differ from what is seen in solid tumors.49,50”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [50]

    The Introduction discusses SV and copy-number signatures as potential BRCAness surrogates in ovarian cancer, and the Discussion describes predicting BRCA deficiency in breast and ovarian cancer. Neither passage addresses indel and structural-variant patterns in myeloma with germline or somatic BRCA inactivation; searches for BRCA, indels, and homologous-recombination deficiency found no such comparison in our copy. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Maclachlan, K. H., Rustad, E. H., Derkach, A., Zheng-Lin, B., Yellapantula, V., Diamond, B., Hultcrantz, M., Ziccheddu, B., Boyle, E. M., Blaney, P., Bolli, N., Zhang, Y., Dogan, A., Lesokhin, A. M., Morgan, G. J., Landgren, O., & Maura, F.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Oslo University Hospital (NO)
  • University of Miami (US)
  • NYU Langone Health (US)
  • University of Milan (IT)
Corresponding author
Maura, Francesco
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-08-27
Volume
12
Issue
1
Pages
5172-5172
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-25469-8
PMC
PMC8397708
OpenAlex
W3193484507
Cited by
49
References
6
Citations by year
2026: 7 · 2025: 10 · 2024: 9 · 2023: 13 · 2022: 10
FWCI
5.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • 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)
Funders
U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (P30 CA 240139)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
chromothripsis, multiple myeloma, prognostic factors, clinical outcomes, whole genome sequencing, exome sequencing, hematologic malignancies, genomic instability
MeSH terms
Chromothripsis, Whole Genome Sequencing, Exome Sequencing, Humans, Multiple Myeloma, Prognosis, Gene Dosage

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