title: High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis.
abstract: Using allele-specific amplification method (ARMS), a highly sensitive one-stage allele-specific PCR, we have evaluated the incidence of NRAS and KRAS2 activating mutations (codons 12, 13, and 61) in 62 patients with either monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM), primary plasma-cell leukemia (P-PCL), and also in human myeloma cell lines (HMCL). NRAS and/or KRAS2 mutations were found in 54.5% of MM at diagnosis (but in 81% at the time of relapse), in 50% of P-PCL, and in 50% of 16 HMCL. In contrast, the occurrence of such mutations was very low in MGUS and indolent MM (12.50%). Of note, KRAS2 mutations were always more frequent than NRAS. The validity of the technique was assessed by direct sequencing of cell lines and of some patients. Multiple mutations found in two patients were confirmed by subcloning exon PCR amplification products, testing clones with our method, and sequencing them. Thus, these early mutations could play a major role in the oncogenesis of MM and P-PCL.
authors.affiliation: Laboratoire de Génétique Moléculaire, Institut de Biologie, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Bezieau
authors.forename: M C
authors.initials: MC
authors.lastname: Devilder
authors.forename: H
authors.initials: H
authors.lastname: Avet-Loiseau
authors.forename: M P
authors.initials: MP
authors.lastname: Mellerin
authors.forename: D
authors.initials: D
authors.lastname: Puthier
authors.forename: E
authors.initials: E
authors.lastname: Pennarun
authors.forename: M J
authors.initials: MJ
authors.lastname: Rapp
authors.forename: J L
authors.initials: JL
authors.lastname: Harousseau
authors.forename: J P
authors.initials: JP
authors.lastname: Moisan
authors.forename: R
authors.initials: R
authors.lastname: Bataille
mesh_terms: D000483:Alleles; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005787:Gene Frequency; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007952:Leukemia, Plasma Cell / Q000175:diagnosis / Q000235:genetics*; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm