The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF.
KRAS and NRAS exon 3 mutations were significantly associated with the myeloma cohort compared with non-myeloma plasma cell dyscrasias (odds ratio (OR) 9.87, 95% confidence interval (CI) 1.07-90.72, P=0.043 and OR 7.03, 95% CI 1.49-33.26, P=0.014).
Forty-eight newly diagnosed myeloma patients were tested with the panel, which included IGH and six genes that are recurrently mutated in myeloma: NRAS, KRAS, HRAS, TP53, MYC, and BRAF.
These findings identify a significant clinical impact of NRAS mutation in myeloma and demonstrate a clear example of functional differences between the KRAS and NRAS oncogenes.
To assess a possible role in tumor progression, the occurrence and type of K- and N-RAS mutations were determined in purified tumor cells, including samples from patients with premalignant monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and extramedullary plasma cell (PC) tumors (ExPCTs).
Flow cytometric analysis using annexin V and 7-aminoactinomycin D (7AAD) showed that R115777 induced apoptosis of 2 of 3 myeloma cell lines at a concentration of 1.0 x 10(-8) M. R115777 appears to be a potent inducer of apoptosis, and its effects depend on the status of Ras mutation in cloned myeloma cells but not on the status of N-Ras mutation in fresh myeloma cells.
ANBL-6, a myeloma cell line, proliferates in response to interleukin 6 (IL-6) stimulation, coculture with bone marrow stromal cells, and when harboring a constitutively active mutant N-ras gene.
We found that the PT-LPDs are divisible into three distinct categories as follows: (1) plasmacytic hyperplasia: most commonly arise in the oropharynx or lymph nodes, are nearly always polyclonal, usually contain multiple EBV infection events or only a minor cell population infected by a single form of EBV, and lack oncogene and tumor suppressor gene alterations; (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma: may arise in lymph nodes or various extranodal sites, are nearly always monoclonal, usually contain a single form of EBV, and lack oncogene and tumor suppressor gene alterations; and (3) immunoblastic lymphoma or multiple myeloma: present with widely disseminated disease, are monoclonal, contain a single form of EBV, and contain alterations of one or more oncogene or tumor suppressor genes (N-ras gene codon 61 point mutation, p53 gene mutation, or c-myc gene rearrangement).
As the mutation was observed only at the N-RAS oncogene level, it is speculated that N-RAS oncogene activation might play an important role in the progression of multiple myeloma.