Abstract
RAS mutations are frequent in relapsed/refractory multiple myeloma (RRMM) but functional study in primary samples is scanty. Herein, in primary myeloma plasma cells of 17 suspected RRMM, functional activation of RAS signalling was studied by Western blot of phosphorylated ERK1/2 (phospho-ERK1/2). Moreover, activating mutations in KRAS, NRAS, BRAF, and ALK were studied by PCR and bidirectional direct sequencing. Furthermore, methylation of negative RAS signalling regulator genes, RASSF1A and RASD1, were analyzed by methylation-specific PCR. As evidenced by phospho-ERK1/2 over-expression, functional RAS activation was detected in 12 (75.0%) RRMM. Of patients with functional RAS activation, sequencing data showed only seven (58.3%) patients with one each had NRAS Q61H, NRAS Q61K, KRAS G12D, KRAS G12V, KRAS G13D, KRAS Q61P, or BRAF V600E mutation, whereas five (41.7%) patients had no RAS/RAF mutation. Conversely, patients without functional RAS activation had no RAS/RAF mutation. Moreover, none of the patients with functional RAS activation had ALK mutations, or methylation of RASSF1A and RASD1. Collectively, functional activation of RAS signalling was present in majority of RRMM but only about half (58.3%) accountable by RAS/RAF mutations. If verified in larger studies, clinical investigations of MEK inhibitors are warranted regardless of RAS/RAF mutations.
Highlights
Multiple myeloma is an incurable haematological malignancy characterized by neoplastic proliferation of clonal plasma cells in the bone marrow[8]
Of the 12 patients with functional ERK activation, seven (58.3%) showed RAS/RAF mutations with one each had NRAS Q61H, NRAS Q61K, KRAS G12D, KRAS G12V, KRAS G13D, KRAS Q61P, or BRAF V600E mutation [this case was reported in Chim et al.11] (Fig. 1B and Table 1)
The other five patients with functional ERK activation had no RAS/RAF mutation at the selected mutation hotspots, including KRAS/NRAS and BRAF, which account for almost all RAS activation in cancers[1]
Summary
Multiple myeloma is an incurable haematological malignancy characterized by neoplastic proliferation of clonal plasma cells in the bone marrow[8]. Genetic aberrations, such as t(4;14), t(14;16), deletion 17p13, and amplification of 1q21 [amp(1q21)], are associated with poor prognosis[8]. Evidence for functional activation of RAS signalling with over-expression of phospho-ERK1/2 by Western blot in primary myeloma plasma cells is scanty. In a bortezomib- and lenalidomide-refractory myeloma patient, we have shown that constitutive activation of RAS signalling, as evidenced by over-expression of phospho-ERK1/2 by Western blot, was attributed by BRAF V600E but not KRAS/NRAS mutation[11]. Status of RAS signalling activation was correlated with activating mutations in KRAS, NRAS, BRAF, or ALK, amp(1q21), and methylation of RASSF1A and RASD1
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