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Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia

Christopher C Oakes, Rainer Claus, Lei Gu, Yassen Assenov, Jennifer Hüllein, Manuela Zucknick, Matthias Bieg, David Brocks, Olga Bogatyrova, Christopher R Schmidt, Laura Rassenti, Thomas J Kipps, Daniel Mertens, Peter Lichter, Hartmut Dohner, Stephan Stilgenbauer, John C. Byrd, Thorsten Zenz and Christoph Plass
Christopher C Oakes
Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ)
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Rainer Claus
Department of Hematology/Oncology, German Cancer Research Center (DKFZ)
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Lei Gu
Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ)
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Yassen Assenov
Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ)
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Jennifer Hüllein
National Center for Tumor Diseases (NCT)
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Manuela Zucknick
Division of Biostatistics, German Cancer Research Center (DKFZ)
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Matthias Bieg
Theoretical Bioinformatics, German Cancer Research Center (DKFZ)
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David Brocks
Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ)
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Olga Bogatyrova
Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ)
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Christopher R Schmidt
Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ)
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Laura Rassenti
Medicine, University of California, San Diego
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Thomas J Kipps
Moores Cancer Center, University of California, San Diego
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Daniel Mertens
Molecular Genetics, German Cancer Research Center (DKFZ)
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Peter Lichter
Molecular Genetics, German Cancer Research Center (DKFZ)
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Hartmut Dohner
Internal Medicine III, University of Ulm
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Stephan Stilgenbauer
Internal Medicine III, University of Ulm
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John C. Byrd
Medicine, The Ohio State University
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Thorsten Zenz
Department of Translational Oncology, National Center for Tumor Diseases (NCT)
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Christoph Plass
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ)
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  • For correspondence: c.plass@dkfz-heidelberg.de
DOI: 10.1158/2159-8290.CD-13-0349
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Abstract

Although clonal selection by genetic driver aberrations in cancer is well documented, the ability of epigenetic alterations to promote tumor evolution is undefined. We used 450k arrays and next-generation sequencing to evaluate intra-tumor heterogeneity and evolution of DNA methylation and genetic aberrations in chronic lymphocytic leukemia (CLL). CLL cases exhibit vast inter-patient differences in intra-tumor methylation heterogeneity, with genetically clonal cases maintaining low methylation heterogeneity and up to 10 percent of total CpGs in a monoallelically methylated state. Increasing methylation heterogeneity correlates with advanced genetic subclonal complexity. Selection of novel DNA methylation patterns is observed only in cases that undergo genetic evolution, and independent genetic evolution is uncommon and is restricted to low-risk alterations. These results reveal that although evolution of DNA methylation occurs in high-risk, clinically-progressive cases, positive selection of novel methylation patterns entail co-evolution of genetic alteration(s) in CLL.

  • Received July 8, 2013.
  • Revision received December 13, 2013.
  • Accepted December 17, 2013.
  • Copyright © 2013, American Association for Cancer Research.
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Published OnlineFirst December 19, 2013
doi: 10.1158/2159-8290.CD-13-0349

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Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia
Christopher C Oakes, Rainer Claus, Lei Gu, Yassen Assenov, Jennifer Hüllein, Manuela Zucknick, Matthias Bieg, David Brocks, Olga Bogatyrova, Christopher R Schmidt, Laura Rassenti, Thomas J Kipps, Daniel Mertens, Peter Lichter, Hartmut Dohner, Stephan Stilgenbauer, John C. Byrd, Thorsten Zenz and Christoph Plass
Cancer Discov December 19 2013 DOI: 10.1158/2159-8290.CD-13-0349

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Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia
Christopher C Oakes, Rainer Claus, Lei Gu, Yassen Assenov, Jennifer Hüllein, Manuela Zucknick, Matthias Bieg, David Brocks, Olga Bogatyrova, Christopher R Schmidt, Laura Rassenti, Thomas J Kipps, Daniel Mertens, Peter Lichter, Hartmut Dohner, Stephan Stilgenbauer, John C. Byrd, Thorsten Zenz and Christoph Plass
Cancer Discov December 19 2013 DOI: 10.1158/2159-8290.CD-13-0349
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