title: Mutations driving CLL and their evolution in progression and relapse.
abstract: Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.|Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Dan A
authors.initials: DA
authors.lastname: Landau
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm 89081, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Tausch
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Amaro N
authors.initials: AN
authors.lastname: Taylor-Weiner
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|IST Austria (Institute of Science and Technology Austria), Klosterneuburg 3400, Austria.|Program for Evolutionary Dynamics, Harvard University, Cambridge 02138, Massachusetts, USA.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Reiter
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne 50937, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Bahlo
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne 50937, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kluth
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge 02138, Massachusetts, USA.|Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bozic
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Lawrence
authors.affiliation: Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Böttcher
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm 89081, Germany.|Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mertens
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Sougnez
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Rosenberg
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Hess
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm 89081, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Edelmann
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm 89081, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kless
authors.affiliation: Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.affiliation: Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ritgen
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne 50937, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Fink
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne 50937, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge 02138, Massachusetts, USA.|Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm 89081, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne 50937, Germany.|Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne 50931, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm 89081, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.|Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D019143:Evolution, Molecular; D059472:Exome / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D020935:MAP Kinase Signaling System / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011379:Prognosis; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D034443:RNA Transport / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C106285:IKZF3 protein, human; D012269:Ribosomal Proteins; C032643:ribosomal protein S21; D051740:Ikaros Transcription Factor