Mutations driving CLL and their evolution in progression and relapse

Dan A. Landau, Eugen Tausch, Amaro N. Taylor-Weiner, Chip Stewart, Johannes G. Reiter, Jasmin Bahlo, Sandra Kluth, Ivana Bozic, Mike Lawrence, Sebastian Böttcher, Scott L. Carter, Kristian Cibulskis, Daniel Mertens, Carrie L. Sougnez, Mara Rosenberg, Julian M. Hess, Jennifer Edelmann, Sabrina Kless, Michael Kneba, Matthias Ritgen, Anna Fink, Kirsten Fischer, Stacey Gabriel, Eric S. Lander, Martin A. Nowak, Hartmut Döhner, Michael Hallek, Donna Neuberg, Gad Getz (), Stephan Stilgenbauer () and Catherine J. Wu ()
Additional contact information
Dan A. Landau: Broad Institute of Harvard and MIT
Eugen Tausch: Ulm University
Amaro N. Taylor-Weiner: Broad Institute of Harvard and MIT
Chip Stewart: Broad Institute of Harvard and MIT
Johannes G. Reiter: Broad Institute of Harvard and MIT
Jasmin Bahlo: University Hospital
Sandra Kluth: University Hospital
Ivana Bozic: Program for Evolutionary Dynamics, Harvard University
Mike Lawrence: Broad Institute of Harvard and MIT
Sebastian Böttcher: University Hospital of Schleswig-Holstein, Campus Kiel
Scott L. Carter: Broad Institute of Harvard and MIT
Kristian Cibulskis: Broad Institute of Harvard and MIT
Daniel Mertens: Ulm University
Carrie L. Sougnez: Broad Institute of Harvard and MIT
Mara Rosenberg: Broad Institute of Harvard and MIT
Julian M. Hess: Broad Institute of Harvard and MIT
Jennifer Edelmann: Ulm University
Sabrina Kless: Ulm University
Michael Kneba: University Hospital of Schleswig-Holstein, Campus Kiel
Matthias Ritgen: University Hospital of Schleswig-Holstein, Campus Kiel
Anna Fink: University Hospital
Kirsten Fischer: University Hospital
Stacey Gabriel: Broad Institute of Harvard and MIT
Eric S. Lander: Broad Institute of Harvard and MIT
Martin A. Nowak: Program for Evolutionary Dynamics, Harvard University
Hartmut Döhner: Ulm University
Michael Hallek: University Hospital
Donna Neuberg: Biostatistics and Computational Biology, Dana-Farber Cancer Institute
Gad Getz: Broad Institute of Harvard and MIT
Stephan Stilgenbauer: Ulm University
Catherine J. Wu: Broad Institute of Harvard and MIT

Nature, 2015, vol. 526, issue 7574, 525-530

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15395

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