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 Döhner, Stephan Stilgen, John C. Byrd, Thorsten Zenz, Christoph Plass

    Research output: Contribution to journalArticle

    85 Scopus citations


    Although clonal selection by genetic driver aberrations in cancer is well documented, the ability of epigenetic alterations to promote tumor evolution is undefi ned. We used 450k arrays and next-generation sequencing to evaluate intratumor heterogeneity and evolution of DNA methylation and genetic aberrations in chronic lymphocytic leukemia (CLL). CLL cases exhibit vast interpatient differences in intratumor methylation heterogeneity, with genetically clonal cases maintaining low methylation heterogeneity and up to 10% 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 entails coevolution of genetic alteration(s) in CLL. SIGNIFICANCE: Epigenetic alterations are pervasive in cancer and continually develop during disease progression; however, the mechanisms that promote changes in the tumor epigenome at large are currently undefi ned. The current work provides insight into the coevolution of genetic and epigenetic aberrations and highlights the infl uential role of genetic aberrations in the selection of novel methylation patterns.

    Original languageEnglish (US)
    Pages (from-to)348-361
    Number of pages14
    JournalCancer discovery
    Issue number3
    StatePublished - Mar 2014

    ASJC Scopus subject areas

    • Oncology

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  • Cite this

    Oakes, C. C., Claus, R., Gu, L., Assenov, Y., Hüllein, J., Zucknick, M., Bieg, M., Brocks, D., Bogatyrova, O., Schmidt, C. R., Rassenti, L., Kipps, T. J., Mertens, D., Lichter, P., Döhner, H., Stilgen, S., Byrd, J. C., Zenz, T., & Plass, C. (2014). Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. Cancer discovery, 4(3), 348-361. https://doi.org/10.1158/2159-8290.CD-13-0349