Portal de Periódicos da CAPES

Evolution of DNA Methylation Is Linked to Genetic Aberrations in Chronic Lymphocytic Leukemia

2013; American Association for Cancer Research; Volume: 4; Issue: 3 Linguagem: Inglês

10.1158/2159-8290.cd-13-0349

2159-8290

Christopher C. Oakes, Rainer Claus, Lei Gu, Yassen Assenov, Jennifer Hüllein, Manuela Zucknick, Matthias Bieg, David Brocks, Olga Bogatyrova, Christopher R. Schmidt, Laura Z. Rassenti, Thomas J. Kipps, Daniel Mertens, Peter Lichter, Hartmut Döhner, Stephan Stilgenbauer, John C. Byrd, Thorsten Zenz, Christoph Plass,

Cancer Genomics and Diagnostics

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.