title: Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells.
abstract: Translocations in myeloma are thought to occur solely in mature B cells in the germinal center through class switch recombination (CSR). We used a targeted captured technique followed by massively parallel sequencing to determine the exact breakpoints in both the immunoglobulin heavy chain (IGH) locus and the partner chromosome in 61 presentation multiple myeloma samples. The majority of samples (62%) have a breakpoint within the switch regions upstream of the IGH constant genes and are generated through CSR in a mature B cell. However, the proportion of CSR translocations is not consistent between cytogenetic subgroups. We find that 100% of t(4;14) are CSR-mediated; however, 21% of t(11;14) and 25% of t(14;20) are generated through DH-JH recombination activation gene-mediated mechanisms, indicating they occur earlier in B-cell development at the pro-B-cell stage in the bone marrow. These 2 groups also generate translocations through receptor revision, as determined by the breakpoints and mutation status of the segments used in 10% and 50% of t(11;14) and t(14;20) samples, respectively. The study indicates that in a significant number of cases the translocation-based etiological events underlying myeloma may arise at the pro-B-cell hematological progenitor cell level, much earlier in B-cell development than was previously thought.
authors: Molecular Haematology, Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors: Brian A
authors: BA
authors: Walker
authors: Christopher P
authors: CP
authors: Wardell
authors: David C
authors: DC
authors: Johnson
authors: Martin F
authors: MF
authors: Kaiser
authors: Dil B
authors: DB
authors: Begum
authors: Nasrin B
authors: NB
authors: Dahir
authors: Fiona M
authors: FM
authors: Ross
authors: Faith E
authors: FE
authors: Davies
authors: David
authors: D
authors: Gonzalez
authors: Gareth J
authors: GJ
authors: Morgan
mesh_terms: D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D019457:Chromosome Breakage; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology*; D059765:Homologous Recombination; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics*; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains