title: Molecular characterization of immunoglobulin gene rearrangements in diffuse large B-cell lymphoma: antigen-driven origin and IGHV4-34 as a particular subgroup of the non-GCB subtype.
abstract: The pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains partially unknown. The analysis of the B-cell receptor of the malignant cells could contribute to a better understanding of the DLBCL biology. We studied the molecular features of the immunoglobulin heavy chain (IGH) rearrangements in 165 patients diagnosed with DLBCL not otherwise specified. Clonal IGH rearrangements were amplified according to the BIOMED-2 protocol and PCR products were sequenced directly. We also analyzed the criteria for stereotyped patterns in all complete IGHV-IGHD-IGHJ (V-D-J) sequences. Complete V-D-J rearrangements were identified in 130 of 165 patients. Most cases (89%) were highly mutated, but 12 sequences were truly unmutated or minimally mutated. Three genes, IGHV4-34, IGHV3-23, and IGHV4-39, accounted for one third of the whole cohort, including an overrepresentation of IGHV4-34 (15.5% overall). Interestingly, all IGHV4-34 rearrangements and all unmutated sequences belonged to the nongerminal center B-cell-like (non-GCB) subtype. Overall, we found three cases following the current criteria for stereotyped heavy chain VH CDR3 sequences, two of them belonging to subsets previously described in CLL. IGHV gene repertoire is remarkably biased, implying an antigen-driven origin in DLBCL. The particular features in the sequence of the immunoglobulins suggest the existence of particular subgroups within the non-GCB subtype.
authors.affiliation: Department of Hematology, University Hospital of Salamanca, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sebastián
authors.forename: Miguel
authors.initials: M
authors.lastname: Alcoceba
authors.forename: Ana
authors.initials: A
authors.lastname: Balanzategui
authors.forename: Luis
authors.initials: L
authors.lastname: Marín
authors.forename: Santiago
authors.initials: S
authors.lastname: Montes-Moreno
authors.forename: Teresa
authors.initials: T
authors.lastname: Flores
authors.forename: David
authors.initials: D
authors.lastname: González
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Sarasquete
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Chillón
authors.forename: Noemí
authors.initials: N
authors.lastname: Puig
authors.forename: Rocío
authors.initials: R
authors.lastname: Corral
authors.forename: Emilia
authors.initials: E
authors.lastname: Pardal
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martín
authors.forename: Eva
authors.initials: E
authors.lastname: González-Barca
authors.forename: M Dolores
authors.initials: MD
authors.lastname: Caballero
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Sanz
authors.forename: Marcos
authors.initials: M
authors.lastname: González
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics; D000951:Antigens, Neoplasm / Q000276:immunology*; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics*; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology; D060152:V(D)J Recombination / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D000596:Amino Acids; D000951:Antigens, Neoplasm; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region