title: Novel secondary Ig VH gene rearrangement and in-frame Ig heavy chain complementarity-determining region III insertion/deletion variants in de novo follicular lymphoma.
abstract: Human germinal center B cell tumors retain the ability of their nontransformed counterparts to somatically hypermutate Ig V genes by nucleotide substitution. Among a survey of 60 primary previously untreated, clonal, follicular lymphomas we have identified a rare V(H) rearrangement variant and two other in-frame nucleotide insertion/deletion variants within complementarity-determining region III of the Ig heavy chain. The neoplastic origin of the V(H) rearrangement variant was directly demonstrated in cells isolated by microdissection from malignant follicles. In all three cases a common clonal origin for the variants was demonstrated by complementarity-determining region III nucleotide sequence homology and shared somatic mutations in germline encoded positions in framework region IV. The monoclonal nature of the tumors was independently confirmed by demonstrating a single t(14;18) translocation breakpoint in the two cases with a detectable translocation. All the variants occurred in functional V(H) rearrangements, which in two cases were directly shown to encode functional Ab molecules. Both recombination-activating genes 1 and 2 were expressed in lymph node tumor cells containing the V(H) rearrangement variant, although recombination-activating gene expression among a panel of lymphomas was not limited to this variant.
authors.affiliation: Intramural Research Support Program, Science Applications International Corp.-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kobrin
authors.forename: M
authors.initials: M
authors.lastname: Bendandi
authors.forename: L
authors.initials: L
authors.lastname: Kwak
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002469:Cell Separation; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics / Q000276:immunology; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000096:biosynthesis / Q000235:genetics*; D016172:DNA Fingerprinting; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005784:Gene Amplification; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D014644:Genetic Variation / Q000276:immunology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007144:Immunoglobulin J-Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000276:immunology*; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D016364:Reading Frames / Q000235:genetics / Q000276:immunology*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000276:immunology*; D014178:Translocation, Genetic; D019895:Transposases / Q000235:genetics
chemical_list: D022801:Complementarity Determining Regions; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007143:Immunoglobulin Heavy Chains; D007144:Immunoglobulin J-Chains; D007135:Immunoglobulin Variable Region; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D012333:RNA, Messenger; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D019895:Transposases