Article of the week: Genetic changes associated with the evolution of Monoclonal Gammopathy of Unknown Significance (MGUS)

For this week’s Article of the Week we have chosen a review article published in the British Journal of Haematology co-authored by MSAG member Dr Andrew Zannettino. This review focuses on the genetic changes associated with the evolution of Monoclonal Gammopathy of Unknown Significance (MGUS) and the progression to Multiple Myeloma (MM).

Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma focuses on three models of MM evolution, the linear, the expansionist and the intraclonal heterogeneity models. It also discusses the newer Next Generation Sequencing (NGS) techniques which are enabling the identification of critical disease mutations. These techniques have thus far demonstrated that there is no single mutation or combination of mutations which are common to all myeloma cells at presentation and therefore that it is likely that multiple mutations and molecular pathways are involved in the evolution of multiple myeloma. From available cytogenetic and NGS studies, the results provide evidence for multiple models and this review postulates and discusses three individual models of myeloma development.

The linear model of tumour evolution follows classical cancer biology theory where tumours are derived from a unicellular origin with clonal growth pattern as a result of sequential accumulation of genetic mutations. This model has been supported by evidence from whole exam sequencing (WES) and whole genome sequencing (WGS) studies comparing normal plasma cells with myeloma cells as well as plasma calls through pre-malignant myeloma stages. These studies demonstrated that with progression from normal plasma cells through to  MGUS cells, smouldering myeloma cells (SMM), myeloma cells and plasma cell leukaemia cells, an increased number of non-synonymous single nucleotide variations (NS-SNVs) was found. These findings suggest that the sequential acquisition of NS-SNVs leads to uncontrolled proliferation of plasma cells and therefore to disease progression.

The expansionist model of tumour evolution suggests that all necessary mutations are already present in plasma cells at the MGUS disease stage and that it is the subsequent expansion of these cells that leads to disease progression. This model is supported by studies using fluorescence in city hybridisation (FISH) analysis which have identified a number of translocations, deletions and gain of function mutations which are in common in MGUS, SMM and MM cells. A number of studies have found that it is the number of plasma cells with these mutations that increased with disease progression, suggesting that selective advantages led to clonal expansion. Additionally, mutations thought previously to be specific to MM cells have now been identified in minor sub-clones at the MGUS stage and it has been demonstrated that there is little change in the number of NS-SNVs present between SMM and MM. The findings of these studies infer that it is not a sequential acquisition of mutations but rather the clonal expansion of existing mutated cells that initiates MM disease progression.

Finally, the intraclonal heterogeneity model of tumour evolution suggests a ‘Darwinian’ competition occurs between existing clonal cells with outgrowth of dominant plasma cell sub-clones leading to MM disease progression. WGS and WES studies have found frequent significant mutations or ‘driver’ genes within a diverse landscape where

many different clones and sub clones arise and co-exist in MM evolution. It is hypothesised that these ‘driver’ genes produce a genetic advantage or dominance of certain clones and that therefore myeloma evolves in a branching fashion with mutations identifiable as sub-clones of existing clones. Studies which support this model have identified recurrently mutated genes in MM evolution which act as ‘driver genes’ including KRAS, NRAS, TP53, BRAF, FAM46C and DIS3. Interestingly these mutated ‘driver’ genes can also be seen in less dominant sub-clone populations suggesting that these mutations can occur later in disease progression. The authors highlight that this is an important finding, as if a therapeutic choice is made to target a particular ‘driver’ gene, this may not be as effective if this gene were present only in a sub-clonal population.

The above provides a summary of the three postulated models for myeloma development. This review also includes in-depth discussion of  novel genetic analysis techniques including single cell analysis as well as epigenetic. Additionally this review emphasises the impact of updated evidence of MM evolution may have on current therapies and suggests that clonal evolution and disease progression should be considered from the initiation of treatment. It also highlights the need for further studies on the changes in clonal architecture associated with MM treatments, as it is likely these studies would heavily influence the development of new treatment strategies.


View the full article and accompanying editorial here: