title: Detection of N-Ras codon 61 mutations in subpopulations of tumor cells in multiple myeloma at presentation.
abstract: Activating point mutations in codons 12, 13, or 61 of the K-ras and N-ras genes have been reported to occur in up to 40% of patients with multiple myeloma at presentation. In a study of 34 presentation myeloma cases using a sensitive polymerase chain reaction-restriction fragment length polymorphism strategy on enriched tumor cell populations, the present study detected N-ras codon 61 mutation-positive cells in all patients. Quantitative plaque hybridization using allele-specific oligonucleotide probes showed that in the majority of patients, ras mutation-positive cells comprise only a subpopulation of the total malignant plasma cell compartment (range, 12%-100%). Using clonospecific point mutations in the 5' untranslated region of the BCL6 gene to quantitate clonal B cells in FACS-sorted bone marrow populations from 2 patients, the representation of ras mutation-positive cells was independent of immunophenotype. These observations imply that mutational activation of N-ras codon 61 is a mandatory event in the pathogenesis of multiple myeloma; such mutations provide a marker of intraclonal heterogeneity that may originate at an earlier ontologic stage than immunophenotypic diversification of the malignant B cell clone.
authors.affiliation: CRC Gene Regulation Group, Paterson Institute for Cancer Research, and CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom.
authors.forename: N
authors.initials: N
authors.lastname: Kalakonda
authors.forename: D G
authors.initials: DG
authors.lastname: Rothwell
authors.forename: J H
authors.initials: JH
authors.lastname: Scarffe
authors.forename: J D
authors.initials: JD
authors.lastname: Norton
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D019943:Amino Acid Substitution; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002999:Clone Cells / Q000737:chemistry / Q000473:pathology; D003062:Codon / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D011905:Genes, ras; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020125:Mutation, Missense; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000473:pathology; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; D003062:Codon; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors