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Leukemia. 2014 Feb;28(2):384-390. doi: 10.1038/leu.2013.199. Epub 2013 Jul 2.

Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms.

Author information

1
Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
2
Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.
3
Department of Hematology of the University Hospital of Salamanca; Centro de Investigacion del Cancer (CIC) de Salamanca; and Instituto Biosanitario de Salamanca (IBSAL); Salamanca, Spain.
4
Illumina Cambridge Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, UK.
5
Targeted Myeloma Treatment, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, UK.
#
Contributed equally

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.

PMID:
23817176
PMCID:
PMC3916874
DOI:
10.1038/leu.2013.199
[Indexed for MEDLINE]
Free PMC Article

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