Abstract
In this study, we analyzed the prevalence and clone size of BRAF V600E mutation in 209 patients with multiple myeloma and related the results to clinical phenotype, response and survival. Biopsies were screened for BRAF V600E by allele-specific real-time PCR (AS-PCR). Positive results were confirmed by immunohistochemistry, Sanger sequencing and, in three patients from whom we had stored purified myeloma cells, whole-exome sequencing. Eleven patients (5.3%) were BRAF V600E mutation positive by AS-PCR and at least one other method. The fraction of mutated cells varied from 4 to 100%. BRAF V600E-positive patients had no characteristic clinical phenotype except for significantly higher levels of serum creatinine (125 versus 86 μmol/l) Seven of eleven patients responded with at least very good partial response to alkylators, immunomodulatory agents or proteasome inhibitors. Progression-free and overall survival were similar in patients with and without the mutation. By this integrated approach, we found that patients with BRAF V600E mutation responded very well to broad acting drugs and there was no relation to prognosis in early-stage myeloma. In particular, a large mutated cell fraction did not correlate with aggressive disease.
Highlights
The oncogenic BRAF V600E mutation causes constitutive activation of the Ras-Raf-MEK-ERK (RAS) signaling pathway, stimulating cellular growth, differentiation and survival.[1]
Prevalence of BRAF V600E mutation BRAF V600E was detected by allele-specific real-time PCR (AS-PCR) in bone marrow or extra medullary disease (EMD) from 11 out of 209 patients (5.3%) with multiple myeloma (Table 1)
Two additional patients with positive BRAF V600E AS-PCR were classified as negative because the mutation was not confirmed by another method
Summary
The oncogenic BRAF V600E mutation causes constitutive activation of the Ras-Raf-MEK-ERK (RAS) signaling pathway, stimulating cellular growth, differentiation and survival.[1]. Lohr et al recently published a genome sequencing study of 203 multiple myeloma patients, highlighting the vast genetic heterogeneity of this disease.[11] BRAF V600E appeared in both major and minor clones, but rarely in the entire tumor cell population.[11,12] When a myeloma patient is exposed to various treatment regimens, a changing and unpredictable pattern of clonal resistance and dominance may occur.[13,14] It has been suggested that myeloma subclones harboring BRAF V600E might have a survival advantage, and that once the BRAF V600E clone becomes dominant, the disease becomes more aggressive.[8,9]. The biological and clinical significance of this mutation is by no means clarified In this retrospective study, we have analyzed. Patients carrying the BRAF V600E mutation and their relation to clinical phenotype, treatment response and survival
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