title: KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype.
abstract: To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Clipson
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: de Leval
authors.affiliation: Department of Cellular Pathology, Southampton University Hospitals National Health Service Trust, Southampton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ashton-Key
authors.affiliation: Department of Histopathology, Royal Marsden Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK [2] Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Vassiliou
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK [2] Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: N
authors.initials: N
authors.lastname: Bolli
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: C
authors.initials: C
authors.lastname: Grove
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Moody
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: L
authors.initials: L
authors.lastname: Escudero-Ibarz
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Gundem
authors.affiliation: Department of Molecular Genetics, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: K
authors.initials: K
authors.lastname: Brugger
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: X
authors.identifier: 0000000278426883
authors.initials: X
authors.lastname: Xue
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: E
authors.initials: E
authors.lastname: Mi
authors.affiliation: Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Bench
authors.affiliation: Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Scott
authors.affiliation: Molecular Malignancy Laboratory, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Follows
authors.affiliation: Division of Oncology, Center for Applied Medical Research CIMA, University of Navarra, Pamplona, Spain.
authors.forename: E F
authors.initials: EF
authors.lastname: Robles
authors.affiliation: Division of Oncology, Center for Applied Medical Research CIMA, University of Navarra, Pamplona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Martinez-Climent
authors.affiliation: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: D
authors.initials: D
authors.lastname: Oscier
authors.affiliation: 1] Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK [2] Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Watkins
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: M-Q
authors.initials: MQ
authors.lastname: Du
mesh_terms: D001706:Biopsy; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D059472:Exome; D016368:Frameshift Mutation; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D014644:Genetic Variation; D005838:Genotype; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008223:Lymphoma / Q000378:metabolism; D018442:Lymphoma, B-Cell, Marginal Zone / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051883:Receptor, Notch2 / Q000378:metabolism; D012008:Recurrence; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013160:Splenic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D053468:CARD Signaling Adaptor Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C497764:NOTCH2 protein, human; D009687:Nuclear Proteins; D051883:Receptor, Notch2; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C426242:CARD11 protein, human; D006162:Guanylate Cyclase