title: Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas.
abstract: Activation of an oncogene via its juxtaposition to the IGH locus by a chromosomal translocation or, less frequently, by genomic amplification is considered a major mechanism of B-cell lymphomagenesis. However, amplification of an IGH/oncogene fusion, coined a complicon, is a rare event in human cancers and has been associated with poor outcome and resistance to treatment. In this article are descriptions of two cases of germinal-center-derived B-cell lymphomas with IGH/BCL2 fusion that additionally displayed amplification of an IGH/MYC fusion. As shown by fluorescence in situ hybridization, the first case contained a IGH/MYC complicon in double minutes, whereas the second case showed a BCL2/IGH/MYC complicon on a der(8)t(8;14)t(14;18). Additional molecular cytogenetic and mutation analyses revealed that the first case also contained a chromosomal translocation affecting the BCL6 oncogene and a biallelic inactivation of TP53. The second case harbored a duplication of REL and acquired a translocation affecting IGL and a biallelic inactivation of TP53 during progression. Complicons affecting Igh/Myc have been reported previously in lymphomas of mouse models simultaneously deficient in Tp53 and in genes of the nonhomologous end-joining DNA repair pathway. To the best of our knowledge, this is the first time that IGH/MYC complicons have been reported in human lymphomas. Our findings imply that the two mechanisms resulting in MYC deregulation, that is, translocation and amplification, can occur simultaneously.
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Germany.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Odero
authors.forename: Roberto
authors.initials: R
authors.lastname: Hernandez
authors.forename: Juan Cruz
authors.initials: JC
authors.lastname: Cigudosa
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Borja
authors.initials: B
authors.lastname: Saez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sanz-García
authors.forename: María T
authors.initials: MT
authors.lastname: Ardanaz
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Novo
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: María José
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
mesh_terms: D000328:Adult; D004268:DNA-Binding Proteins / Q000235:genetics; D005784:Gene Amplification; D019254:Genes, bcl-2; D016259:Genes, myc; D020573:Genes, rel; D018858:Germinal Center; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53