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Nat Commun. 2018 Aug 22;9(1):3363. doi: 10.1038/s41467-018-05058-y.

Genomic patterns of progression in smoldering multiple myeloma.

Author information

1
Department of Oncology and Hemato-Oncology, University of Milan, Milan, 20122, Italy.
2
Department of Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133, Italy.
3
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK.
4
CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, 44035, France.
5
CHU de Nantes, Nantes, 44093, France.
6
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02215, MA, USA.
7
Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
8
Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
9
Genomics of Myeloma Laboratory, L'Institut Universitaire du Cancer Oncopole, Toulouse, 31100, France. avet-loiseau.h@chu-toulouse.fr.
10
Department of Oncology and Hemato-Oncology, University of Milan, Milan, 20122, Italy. pc8@sanger.ac.uk.
11
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02215, MA, USA. nikhil_munshi@dfci.harvard.edu.
12
Veterans Administration Boston Healthcare System, West Roxbury, 02132, MA, USA. nikhil_munshi@dfci.harvard.edu.

Abstract

We analyzed whole genomes of unique paired samples from smoldering multiple myeloma (SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a "static progression model", where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects the time needed to accumulate a sufficient disease burden; and a "spontaneous evolution model", where a change in the subclonal composition is observed. We also observe that activation-induced cytidine deaminase plays a major role in shaping the mutational landscape of early subclinical phases, while progression is driven by APOBEC cytidine deaminases. These results provide a unique insight into myelomagenesis with potential implications for the definition of smoldering disease and timing of treatment initiation.

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