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Cancer Discov. 2014 Mar;4(3):348-61. doi: 10.1158/2159-8290.CD-13-0349. Epub 2013 Dec 19.

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

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Divisions of 1Epigenomics and Cancer Risk Factors, 2Theoretical Bioinformatics, 3Biostatistics, and 4Molecular Genetics; 5Department of Translational Oncology, National Center for Tumor Diseases (NCT), The German Cancer Research Center (DKFZ); 6Department of Medicine V, University of Heidelberg, Heidelberg; 7Department of Medicine, University of Freiburg Medical Center, Freiburg; 8Department of Internal Medicine III, University of Ulm, Ulm; 9The German Cancer Consortium, Germany; 10Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, California; and 11Division of Hematology, The Ohio State University, Columbus, Ohio.


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 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.

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