title: Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing.
abstract: OBJECTIVE
  Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.
  
  
  METHODS
  We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.
  
  
  RESULTS
  We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02-4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05-4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08-5.2; P = 0.03).
  
  
  CONCLUSIONS
  We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Parry
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Matthew Jj
authors.initials: MJ
authors.lastname: Rose-Zerilli
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Viktor
authors.initials: V
authors.lastname: Ljungström
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Renata
authors.initials: R
authors.lastname: Walewska
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Parker
authors.affiliation: Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Anton
authors.initials: A
authors.lastname: Parker
authors.affiliation: Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Zadie
authors.initials: Z
authors.lastname: Davis
authors.affiliation: Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Gardiner
authors.affiliation: Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: McIver-Brown
authors.affiliation: Department of Hematology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Kalpadakis
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece.
authors.forename: Aliki
authors.initials: A
authors.lastname: Xochelli
authors.affiliation: Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.affiliation: Division of Molecular Oncology, Department of Onco-Haematology, IRCCS Istituto Scientifico San Raffaele, Fondazione Centro San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fazi
authors.affiliation: Heamato-oncology Unit, Division of Molecular Pathology, Institute for Cancer Research, Sutton, UK.
authors.forename: David Gonzalez
authors.initials: DG
authors.lastname: de Castro
authors.affiliation: Heamato-oncology Unit, Division of Molecular Pathology, Institute for Cancer Research, Sutton, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Dearden
authors.affiliation: School of Cancer Studies, University of Birmingham, Birmingham, UK; Department of Haematology, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashton-Key
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Genetic Epidemiology and Bioinformatics, Faculty of Medicine, University of Southampton, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Collins
authors.affiliation: Division of Molecular Oncology, Department of Onco-Haematology, IRCCS Istituto Scientifico San Raffaele, Fondazione Centro San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Haematopathology Unit, Hospital Clinic, Barcelona University, Villarroel, Barcelona, Spain.
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.affiliation: Department of Hematology, Athens Medical Center, Athens, Greece.
authors.forename: Gerassimos
authors.initials: G
authors.lastname: Pangalis
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece.|Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.|Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D018442:Lymphoma, B-Cell, Marginal Zone / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D051883:Receptor, Notch2 / Q000235:genetics; D012307:Risk Factors; D013160:Splenic Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; C096161:KLF2 protein, human; C120898:KMT2D protein, human; D051741:Kruppel-Like Transcription Factors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C497764:NOTCH2 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D051883:Receptor, Notch2; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3