Abstract
Multiple myeloma (MM) is a clinically and genetically heterogeneous plasma cell (PC) malignancy. Whole-exome sequencing has identified therapeutically targetable mutations such as those in the mitogen-activated protein kinase (MAPK) pathway, which are the most prevalent MM mutations. We used deep sequencing to screen 167 representative patients with PC dyscrasias [132 with MM, 24 with primary PC leukemia (pPCL) and 11 with secondary PC leukemia (sPCL)] for mutations in BRAF, NRAS and KRAS, which were respectively found in 12%, 23.9% and 29.3% of cases. Overall, the MAPK pathway was affected in 57.5% of the patients (63.6% of those with sPCL, 59.8% of those with MM, and 41.7% of those with pPCL). The majority of BRAF variants were comparably expressed at transcript level. Additionally, gene expression profiling indicated the MAPK pathway is activated in mutated patients. Finally, we found that vemurafenib inhibition of BRAF activation in mutated U266 cells affected the expression of genes known to be associated with MM. Our data confirm and extend previous published evidence that MAPK pathway activation is recurrent in myeloma; the finding that it is mediated by BRAF mutations in a significant fraction of patients has potentially immediate clinical implications.
Highlights
Multiple myeloma (MM) is a malignant disorder characterized by the clonal proliferation of bone marrow (BM) plasma cells (PCs)
In order to estimate the frequency of BRAF mutations in different forms of PC dyscrasias, 167 specimens (132 MM, 24 primary plasma cell leukemia (PCL) (pPCL) and 11 secondary PCL (sPCL)) and 21 human myeloma cell lines (HMCLs) underwent next-generation sequencing (NGS) of the mutational hot-spots, namely exons 11 and 15 (Cosmic Release v70, at http:// cancer.sanger.ac.uk/cancergenome/projects/cosmic/)
Mutations were detected in 10.6% of the patients with MM at onset (14/132), 20.8% of pPCLs (5/24) and 9.1% of sPCLs (1/11)
Summary
Multiple myeloma (MM) is a malignant disorder characterized by the clonal proliferation of bone marrow (BM) plasma cells (PCs). The genetic background and clinical course of the disease are highly heterogeneous, ranging from pre-malignant monoclonal gammopathy of undetermined significance to smoldering MM, symptomatic MM, and extra-medullary MM/plasma cell leukemia (PCL) [1]. Recent therapeutic advances have extended overall patient survival, but current anti-MM treatments are not specific and act by means of pleiotropic mechanisms. Along with already known NRAS and KRAS mutations, these include BRAF mutations, which have been recently reported to occur in 4-15% of patients [46] and may be of potentially immediate clinical relevance because of the availability of effective BRAF inhibitors that are being investigated in MM treatment [7,8,9]
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