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Nat Commun. 2014;5:2997. doi: 10.1038/ncomms3997.

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

Author information

1
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Haematology, University of Cambridge, CIMR, Cambridge CB2 0XY, UK.
2
1] Unité de Génomique du Myélome, CHU Rangueil, Toulouse 31059, France [2] CRCT, INSERM U1037, Toulouse 31400, France.
3
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
4
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Human Genetics, VIB and University of Leuven, Leuven 3000, Belgium.
5
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton CB10 1SA, UK.
6
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Medical Genetics, Addenbrooke's Hospital NHS Trust, Cambridge CB2 0QQ, UK.
7
Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
8
1] Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Boston Veterans Administration Healthcare System, West Roxbury, Massachusetts 02132, USA.
9
Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.
10
1] Center for Cancer Research Nantes-Angers, UMR 892 Inserm-6299 CNRS-University of Nantes, IRS-UN, Nantes 4407, France [2] UMGC, University Hospital, Nantes 44093, France.
11
Department of Hematology, University Hospital, Nantes 44093, France.
12
Department of Hematology, University Hospital and CRCT, INSERM U1037, Toulouse 31400, France.
13
Department of Hematology, University Hospital, Lille 59045, France.
14
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2].

Abstract

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.

PMID:
24429703
PMCID:
PMC3905727
DOI:
10.1038/ncomms3997
[Indexed for MEDLINE]
Free PMC Article

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