Finding genetic changes that lead from MGUS to myeloma
Cancer arises fundamentally from mutations in genes throughout the tumour genome, and may progress by accruing further somatic mutations. It is now feasible, using next generation DNA sequencing, to be able to map any mutation in functionally relevant genes across the genome. In any specific cancer type, the question remains how mutations differ between individual patients and, importantly between tumour cells in any given patient, termed intraclonal heterogeneity. We will examine intraclonal heterogeneity across the genome in a benign condition called monoclonal gammopathy of undetermined significance (MGUS), which almost invariably precedes evolution of malignant multiple myeloma (MM), a blood cancer of plasma cells. We will do this by carrying our genome-wide DNA sequencing in single cells derived from serial progression of MGUS to MM in a paired case, at both disease stages comparing findings with the bulk tumour populations. These findings will allow us to model the nature of different cells at the earliest stage of disease in MGUS, and whether subclonal competition is involved in progression to the MM cancer state. Finally, the project will seek to examine DNA motifs in genes that may be preferentially targeted to identify putative mutational mechanisms.