title: Genomic profiling of Richter's syndrome: recurrent lesions and differences with de novo diffuse large B-cell lymphomas.
abstract: Richter's syndrome (RS) represents the transformation of chronic lymphocytic leukaemia (CLL) to aggressive lymphoma and is mostly represented by diffuse large B-cell lymphoma (DLBCL), with a post-germinal centre (GC) phenotype, clonally related to the pre-existing CLL. RS has a very poor prognosis and its pathogenetic mechanisms are poorly understood. In order to gain additional hints in RS pathogenesis, we performed a genome-wide DNA profiling study of 13 RS phases and eight matched CLL phases using the Affymetrix Human Mapping 250K NspI SNP arrays. Individual genomic profiles were heterogeneous, with no individual lesions occurring in more than half of the cases. However, several observations suggest that MYC pathway might be involved in RS. The 13q13.3-qter region containing MIRHG1 (MIR-17-92), a cluster of microRNA interacting with c-MYC, was acquired at the time of transformation. The 13q gain was coupled with the gain of c-MYC and loss of TP53. Translocation of c-MYC was acquired at transformation in a fraction of cases and this event appeared mutually exclusive with gain of MIRHG1. MYCN, a c-MYC homologue, was also recurrently gained. By comparing RS with 48 de novo DLBCL, RS presented a significantly lower prevalence of deletions affecting the PRDM1 and TNFAIP3, genes on 6q, known to be associated with a post-GC phenotype. In conclusion, the genomic profile of RS seems to differ from what observed in de novo DLBCL and in other transformed DLBCL. Genomic lesions occurring in RS are heterogeneous suggesting the existence of different RS subsets, possibly due to different transforming mechanisms. A deregulation of MYC pathway might represent one of the main transformation events in the pathogenesis of a subset of RS clonally related to the previous CLL.
authors.affiliation: Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
authors.forename: Marta
authors.initials: M
authors.lastname: Scandurra
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Clara
authors.initials: C
authors.lastname: Deambrogi
authors.forename: Paola M V
authors.initials: PM
authors.lastname: Rancoita
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Chigrinova
authors.forename: Michael
authors.initials: M
authors.lastname: Mian
authors.forename: Michaela
authors.initials: M
authors.lastname: Cerri
authors.forename: Silvia
authors.initials: S
authors.lastname: Rasi
authors.forename: Elisa
authors.initials: E
authors.lastname: Sozzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Santiago M
authors.initials: SM
authors.lastname: Moreno
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
mesh_terms: D002869:Chromosome Aberrations; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004268:DNA-Binding Proteins; D018450:Disease Progression; D020869:Gene Expression Profiling; D015322:Gene Rearrangement, B-Lymphocyte; D016259:Genes, myc; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012008:Recurrence; D012097:Repressor Proteins / Q000235:genetics; D017384:Sequence Deletion; D013577:Syndrome; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3