title: Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome.
abstract: Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ∼20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ∼30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.
authors.affiliation: Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, 2 Department of Pathology and Cell Biology, 3 Departments of Genetics and Development and of Microbiology and Immunology and 4 Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fabbri
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.forename: Jiguang
authors.initials: J
authors.lastname: Wang
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002872:Chromosome Deletion; D002999:Clone Cells; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D013577:Syndrome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C539004:CDKN2AIP protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53