Multiple myeloma is a malignancy of antibody-producing white blood cells known as plasma cells. Although it is essentially incurable, therapies are improving and many patients now survive for five years or longer. The pathogenesis of this cancer and the genetic lesions most often involved are not yet well understood. The myeloma cells of about 40% of patients are known to harbour chromosome translocations that result in the over-expression of one or more genes; other chromosome abnormalities are also common. These changes, however, cannot be sufficient for cancer development as they are also found in pre-malignant plasma cells.

In order to understand the genetic basis of myeloma development more fully, a large, international group of researchers and clinicians led by Gad Getz and Todd Grubb of the Broad Institute, Cambridge, Massachusetts, USA has now sequenced the genomes of myeloma cells from thirty-eight patients. The complete genomes were sequenced in 23 of the cases and the exomes (coding genomes) in the remaining 15 and in one patient whose genome was analysed using both approaches. The cancer cell genomes were compared to those obtained from paired normal DNA to differentiate cancer-specific changes from germline mutations. As expected, all sequences showed mutations occurring most often at CpG dinucleotides, and the complete genome sequences showed lower mutation densities in coding DNA than in introns and intergenic regions.

It can be assumed that genes found to be frequently mutated in this set of myeloma genomes may be associated with mechanisms of carcinogenesis. Mutations were frequently observed in a number of genes associated with RNA processing and protein translation, protein folding, histone methylation and blood coagulation. Three genes linked to protein translation – DIS3, which encodes the catalytic component of the exosome complex that regulates RNA processing; FAM46C, which encodes a protein that is believed to be involved in regulating protein translation; and LRRK2, a kinase involved in the initiation of translation – were each mutated in three or more of the myeloma genomes. A link between deregulation of protein homeostasis and myeloma development, as suggested by this finding, is consistent with both the greatly increased immunoglobulin production that is characteristic of myeloma cells and the relative success of the proteasome inhibitor bortezomib in this cancer type.

Mutations were also observed in the histone-modifying gene HOX9 and in eleven different genes in the NF-kB pathway, this latter finding indicating that this pathway and NF-kB activation may be broadly implicated in myeloma development. Two patients had an identical missense mutation in the gene encoding the interferon regulatory factor IRF4, which is likely to be a gain-of-function mutation in a putative oncogene. One mutation was also observed in the BRAF gene. This finding is of particular clinical interest because the kinase encoded by this gene, a known oncogene, is the target of several promising developmental drugs including PLX4032 for melanoma. To investigate this further, the researchers genotyped 161 additional myeloma patients at this locus and found mutations in seven cases. Four of these harboured the V600E mutation commonly found in melanoma.

Taken together, these results suggest several putative mechanisms of myeloma development, some of which may yield potential drug targets. The identification of BRAF mutations in a small subset of patients suggests that these patients, if identified, might benefit from treatment with inhibitors of this enzyme.

Article:

Chapman, M.A., Lawrence, M.S., Keats, J.J. and 47 others (2011). Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467-472 doi:10.1038/nature09837