Publication Date:
2015-10-16
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Landau, Dan A -- Tausch, Eugen -- Taylor-Weiner, Amaro N -- Stewart, Chip -- Reiter, Johannes G -- Bahlo, Jasmin -- Kluth, Sandra -- Bozic, Ivana -- Lawrence, Mike -- Bottcher, Sebastian -- Carter, Scott L -- Cibulskis, Kristian -- Mertens, Daniel -- Sougnez, Carrie L -- Rosenberg, Mara -- Hess, Julian M -- Edelmann, Jennifer -- Kless, Sabrina -- Kneba, Michael -- Ritgen, Matthias -- Fink, Anna -- Fischer, Kirsten -- Gabriel, Stacey -- Lander, Eric S -- Nowak, Martin A -- Dohner, Hartmut -- Hallek, Michael -- Neuberg, Donna -- Getz, Gad -- Stilgenbauer, Stephan -- Wu, Catherine J -- 1K01ES025431-01/ES/NIEHS NIH HHS/ -- 1R01CA182461-02/CA/NCI NIH HHS/ -- 1R01CA184922-01/CA/NCI NIH HHS/ -- 1U10CA180861-01/CA/NCI NIH HHS/ -- K01 ES025431/ES/NIEHS NIH HHS/ -- R01 HL116452/HL/NHLBI NIH HHS/ -- U10 CA180861/CA/NCI NIH HHS/ -- U54HG003067/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Oct 22;526(7574):525-30. doi: 10.1038/nature15395. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Internal Medicine III, Ulm University, Ulm 89081, Germany. ; IST Austria (Institute of Science and Technology Austria), Klosterneuburg 3400, Austria. ; Program for Evolutionary Dynamics, Harvard University, Cambridge 02138, Massachusetts, USA. ; Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne 50937, Germany. ; Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany. ; Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany. ; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne 50931, Germany. ; Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466571" target="_blank"〉PubMed〈/a〉
Keywords:
Cell Transformation, Neoplastic/genetics
;
Clone Cells/metabolism/pathology
;
DNA Copy Number Variations/genetics
;
*Disease Progression
;
*Evolution, Molecular
;
Exome/genetics
;
Genes, myc/genetics
;
Humans
;
Ikaros Transcription Factor/genetics
;
Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis/*genetics/pathology/therapy
;
MAP Kinase Signaling System/genetics
;
Mutation/*genetics
;
Neoplasm Recurrence, Local/*genetics
;
Prognosis
;
RNA Processing, Post-Transcriptional/genetics
;
RNA Transport/genetics
;
Ribosomal Proteins/genetics
;
Treatment Outcome
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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