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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-02

AUTHORS

Brian A Walker, Christopher P Wardell, Lorenzo Melchor, Annamaria Brioli, David C Johnson, Martin F Kaiser, Fabio Mirabella, Lucia Lopez-Corral, Sean Humphray, Lisa Murray, Mark Ross, David Bentley, Norma C Gutiérrez, Ramón Garcia-Sanz, Jesus San Miguel, Faith E Davies, David Gonzalez, Gareth J Morgan

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. More... »

PAGES

384

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2013.199

DOI

http://dx.doi.org/10.1038/leu.2013.199

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1019463441

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23817176


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