Identification of common and genetic subtype specific molecular programs associated with progression from monoclonal gammopathy of undetermined significance (MGUS) to myeloma (MM)

B60

Events mediating transformation from the pre-malignant MGUS to MM is largely unknown. A number of distinct genetic subtypes of myeloma, with unique clinical, molecular, pathological and genetic associations, exist. In this study, we analyzed the difference in gene expression profile between MGUS and MM of 2 common genetic subtypes of MM, t(11;14) and hyperdiploid MM, separately in a Mayo Clinic cohort using a powerful functional analysis tool called gene set enrichment analysis. The results are then compared for the 2 genetic subtypes to obtain common and subtype-specific progression associated genesets. A predominant and common theme relating to MM progression is the over-expression of proliferation related genes in MM highlighted by the enrichment of gene-sets related to proliferation (either experimentally verified or predicted E2F transcriptional targets based on presence of E2F binding motifs). Another common difference is the enrichment of gene-sets relating to MYC activation. Seven of eight gene-sets related to MYC activation in the database are significantly enriched in MM of both genetic subtypes compared to MGUS. Leading edge (positively correlated genes) analysis of enriched MYC-related genesets and proliferation-related genesets revealed a core, overlapping signature of 7 genes specific to the MYC but not proliferation-related genesets. These genes are further verified as MYC transcriptional targets using Metacore, a network analysis tool. In addition, all the genes were identified as MYC network genes with 6 of them validated by chromatin immunoprecipitation in a prior publication. This signature was not expressed in normal plasma cells, rarely and weakly in MGUS and in about two-thirds of MM. There are some differences that are unique to each genetic subtype. Hyperdiploid MM progression is enriched for testis antigens and hypomethylation-related genesets. This was validated by a separate analysis on the expression of cancer testis antigen in a large combined dataset of Mayo clinic and University of Arkansas (UAMS), showing that cancer testis expression is more common in hyperdiploid MM. On the other hand, t(11;14) MM progression is enriched for genesets related to interferon response and the RAS pathway, which is consistent with our previous findings that activating RAS mutations are more common in t(11;14) MM, and targets of a number of miRNAs, suggesting that t(11;14) progression may be related to reduction of miRNA species, which have been shown to be associated with dedifferentiated state, thereby providing possible explanation for the lymphoplasmacytoid morphology of these tumors. These findings were replicated in an analysis of an independent data from UAMS. Our analysis therefore suggests that MYC activation may be a unifying and critical transformation event in MGUS to MM progression. In addition, it also highlights the fact that different genetic subtypes of MM may follow unique progression pathway.