Prevalence of ras/mapk pathway mutation (KRAS, NRAS, and BRAF) in plasma cell myeloma at a single institute in Korea

Abstract

Background & Aim Multiple myeloma (MM) is a hematologic malignancy characterized by neoplastic proliferation of clonal plasma cells in the bone marrow and its pathogenesis is not fully understood. Recent genomic studies have shown that the RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3) is the most frequently mutated pathway in patients with MM, 40% to 55% of newly diagnosed patients with MM have driver mutations in NRAS or KRAS. About of patients with MM harbored the BRAF mutation at diagnosis, mostly on amino acid V600, increasing to 18% at relapse. To understand the prevalance the somatic mutation of the RAS/MAPK pathway (NRAS, KRAS, and BRAF) in MM, we performed the mutation analysis from 50 patients with MM. Methods, Results & Conclusion All bone marrow samples were from initial diagnostic specimens, evaluated by a hematologist at St Mary`s hospital, Seoul, between 2009 and 2012. The clinical and demographic characteristics of the 50 MM patients are summarized in Table 1. BRAF V600E was screened by allele-specific real-time PCR (AS-PCR). Using pyrosequencing, bone marrow were retrospectively analysed for RAS status that is, for mutations within KRAS and NRAS mutation. RAS mutations were detcted in 8(16.0%) of 50 patients, including 4 patients with KRAS mutation (2 patients; G12V, 2 patients; G13D), 4 patients with NRAS mutation (Q61R). Among 4 patients with KRAS mutaion, 1 patient had t(8;14) genetic aberrattion. Among 4 patients with NRAS Q61R mutaion, 3 patients had hyperdiploidy. The point mutations of NRAS and KRAS genes occurs at a rate of 20% of cases of MM. BRAF V600E mutation was detected in 8 (16.0%) of 50 MM patients. In these patients, 4 patients had IgA monoclonal protein and 3 patients had light chain (kappa) monoclonal protein, and 1 patient had IgG(kappa) monoclonal protein. In these patients 3 patients (37.5%, 3/8) had 1q gain, 3 patietns (37.5%, 3/8) had t(11;14), 1 patient (12.5%, 1/8) had t(8;14), and 1 patient (12.5%, 1/8) had add (14)(q32). Compared with BRAF wild type, those carrying the BRAF V600E mutation had higher frequency of IgA, and patients with mutated the BRAF V600E genotype had higher level of calcium (P = 0.0154) and beta-2 microglobulin (P=0.0491) (Table 2). BRAF and RAS mutation screening is important in the molecular diagnostics of MM and it provide a rationale for clinical development of targeted treatment in MM.