title: Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.
abstract: Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Okosun
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.|1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Bödör
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Shamzah
authors.initials: S
authors.lastname: Araf
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Yang
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, USA.|Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, USA.
authors.forename: Chenyi
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Boller
authors.affiliation: Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.affiliation: Genome Centre, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Monika
authors.initials: M
authors.lastname: Bozek
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Sameena
authors.initials: S
authors.lastname: Iqbal
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Janet
authors.initials: J
authors.lastname: Matthews
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Wrench
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Jacek
authors.initials: J
authors.lastname: Marzec
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Kiran
authors.initials: K
authors.lastname: Tawana
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Popov
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Ciaran
authors.initials: C
authors.lastname: O'Riain
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Derville
authors.initials: D
authors.lastname: O'Shea
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Carlotti
authors.affiliation: Cancer Sciences Division, University of Southampton, Southampton, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Davies
authors.affiliation: Oncology Department, Biodonostia Research Institute, San Sebastian, Spain.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lawrie
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Andras
authors.initials: A
authors.lastname: Matolcsy
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Calaminici
authors.affiliation: Department of Histopathology, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Norton
authors.affiliation: Department of Histopathology, Manchester Royal Infirmary, Manchester, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Byers
authors.affiliation: Genome Centre, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Mein
authors.affiliation: Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: T Andrew
authors.initials: TA
authors.lastname: Lister
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin, 13353 Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Montoto
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, USA.|Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Jude
authors.initials: J
authors.lastname: Fitzgibbon
mesh_terms: D001483:Base Sequence; D050882:CREB-Binding Protein / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D059472:Exome / Q000235:genetics; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000503:physiopathology*; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010802:Phylogeny; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; C081976:EBF1 protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C120898:KMT2D protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3