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

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.