Abstract
The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.
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Acknowledgements
We gratefully acknowledge the Institute of Cancer Research Tumour Profiling Unit for their support and technical expertise in this study. This study was supported by grants from the Myeloma UK, Cancer Research UK and the National Institutes of Health Biomedical Research Centre at the Royal Marsden Hospital.
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SH, LM, MR and DB are employed by Illumina Cambridge Ltd. The remaining authors declare no conflict of interest.
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Walker, B., Wardell, C., Melchor, L. et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 28, 384–390 (2014). https://doi.org/10.1038/leu.2013.199
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DOI: https://doi.org/10.1038/leu.2013.199
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