Mutations driving CLL and their evolution in progression and relapse

Landau, Dan A.; Tausch, Eugen; Taylor-Weiner, Amaro N.; Stewart, Chip; Reiter, Johannes G.; Bahlo, Jasmin; Kluth, Sandra; Bozic, Ivana; Lawrence, Mike; Böttcher, Sebastian; Carter, Scott L; Cibulskis, Kristian; Mertens, Daniel; Sougnez, Carrie; 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.; Döhner, Hartmut; Hallek, Michael; Neuberg, Donna; Getz, Gad; Stilgenbauer, Stephan; Wu, Catherine J.

doi:10.1038/nature15395

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Mutations driving CLL and their evolution in progression and relapse

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Author(s): Dan A. Landau ¹ ^, ² ^, ³ ^, ⁴ , Eugen Tausch ⁵ , Amaro N Taylor-Weiner ¹ , Chip Stewart ¹ , Johannes G. Reiter ¹ ^, ² ^, ⁶ ^, ⁸ , Jasmin Bahlo ⁷ ^, ¹⁴ , Sandra Kluth ⁷ ^, ¹⁴ , Ivana Bozic ⁸ ^, ⁹ , Mike Lawrence ¹ , Sebastian Böttcher ¹⁰ , Scott L. Carter ¹ ^, ¹¹ , Kristian Cibulskis ¹ , Daniel Mertens ¹² , Carrie Sougnez ¹ , Mara Rosenberg ¹ , Julian M. Hess ¹ , Jennifer Edelmann ⁵ , Sabrina Kless ⁵ , Michael Kneba ¹⁰ , Matthias Ritgen ¹⁰ , Anna Fink ⁷ ^, ¹³ , Kirsten Fischer ⁷ ^, ¹³ , Stacey Gabriel ¹ , Eric Lander ¹ , Martin A. Nowak ⁸ ^, ⁹ ^, ¹⁴ , Hartmut Döhner ⁵ , Michael Hallek ⁷ ^, ¹³ ^, ¹⁵ , Donna Neuberg ¹⁶ , Gad Getz ¹ ^, ¹⁷ ^, ^† , Stephan Stilgenbauer ⁵ ^, ^† , Catherine J. Wu ¹ ^, ² ^, ³ ^, ⁴ ^, ^†

Publication date (Electronic): 14 October 2015

Journal: Nature

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SUMMARY

Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. We identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized cancer drivers ( RPS15, IKZF3) and collectively identify RNA processing and export, MYC activity and MAPK signaling as central pathways involved in CLL. Clonality analysis of this large dataset 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 datasets of clinically informative samples enable the discovery of novel cancer genes and the network of relationships between the driver events and their impact on disease relapse and clinical outcome.

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Accumulation of driver and passenger mutations during tumor progression.

Ivana Bozic, Tibor Antal, Hisashi Ohtsuki … (2010)

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development-providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small--0.004 ± 0.0004--and has major implications for experimental cancer research.

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The role of chromosomal instability in tumor initiation.

Martin Nowak, Natalia Komarova, Anirvan Sengupta … (2002)

Chromosomal instability (CIN) is a defining characteristic of most human cancers. Mutation of CIN genes increases the probability that whole chromosomes or large fractions of chromosomes are gained or lost during cell division. The consequence of CIN is an imbalance in the number of chromosomes per cell (aneuploidy) and an enhanced rate of loss of heterozygosity. A major question of cancer genetics is to what extent CIN, or any genetic instability, is an early event and consequently a driving force for tumor progression. In this article, we develop a mathematical framework for studying the effect of CIN on the somatic evolution of cancer. Specifically, we calculate the conditions for CIN to initiate the process of colorectal tumorigenesis before the inactivation of tumor suppressor genes.

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Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients.

Hanna T. Gazda, Mee Sheen, Adrianna Vlachos … (2008)

Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital anomalies that are present in approximately 30%-50% of patients. The disease has been associated with mutations in four ribosomal protein (RP) genes, RPS19, RPS24, RPS17, and RPL35A, in about 30% of patients. However, the genetic basis of the remaining 70% of cases is still unknown. Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7. In addition, we identified rare variants of unknown significance in three other genes, RPL36, RPS15, and RPS27A. Remarkably, careful review of the clinical data showed that mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. We also demonstrate that mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway, expanding the repertoire of ribosomal RNA processing defects associated with DBA.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 18 August 2015

Publication date (Electronic): 14 October 2015

Publication date (Print): 22 October 2015

Publication date PMC-release: 22 April 2016

Volume: 526

Issue: 7574

Pages: 525-530

Affiliations

[1 ] Broad Institute of Harvard and MIT, Cambridge, MA

[2 ] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

[3 ] Department of Internal Medicine, Brigham and Women's Hospital, Boston, MA

[4 ] Harvard Medical School, Boston MA

[5 ] Department of Internal Medicine III, Ulm University, Ulm, Germany

[6 ] IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria

[7 ] Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, Germany

[8 ] Program for Evolutionary Dynamics, Harvard University, Cambridge, MA

[9 ] Department of Mathematics, Harvard University, Cambridge, MA

[10 ] Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany

[11 ] Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA

[12 ] German Cancer Research Center (DKFZ), Heidelberg, Germany

[13 ] German CLL Study Group, central office, Cologne.

[14 ] Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA

[15 ] Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD).

[16 ] Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA

[17 ] Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

Author notes

[*]

co-first author

[**]

co-senior author

[† ]Correspondence to: 1. Catherine J. Wu, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston MA, USA 02215, cwu@ 123456partners.org , 2. Stephan Stilgenbauer MD, Department of Internal Medicine III, Ulm University, Ulm, Germany, Stephan.Stilgenbauer@ 123456uniklinik-ulm.de , 3. Gad Getz PhD, Broad Institute, Cambridge MA, gadgetz@ 123456broadinstitute.org

Article

Manuscript ID: NIHMS715090

DOI: 10.1038/nature15395

PMC ID: 4815041

PubMed ID: 26466571

SO-VID: 4471175f-0f83-4503-81ec-d1587fc8f1b3

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Mutations driving CLL and their evolution in progression and relapse

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Crocodylian evolution

Most cited references 21

Accumulation of driver and passenger mutations during tumor progression.

The role of chromosomal instability in tumor initiation.

Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients.

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