Abstract
We examined genetic and epigenetic changes that occur during disease progression from indolent to aggressive forms of chronic lymphocytic leukemia (CLL) using serial samples from 27 patients. Analysis of DNA mutations grouped the leukemia cases into three categories: evolving (26%), expanding (26%) and static (47%). Thus, approximately three-quarters of the CLL cases had little to no genetic subclonal evolution. However, we identified significant recurrent DNA methylation changes during progression at 4752 CpGs enriched for regions near Polycomb 2 repressive complex (PRC2) targets. Progression-associated CpGs near the PRC2 targets undergo methylation changes in the same direction during disease progression as during normal development from naive to memory B cells. Our study shows that CLL progression does not typically occur via subclonal evolution, but that certain CpG sites undergo recurrent methylation changes. Our results suggest CLL progression may involve developmental processes shared in common with the generation of normal memory B cells.
Highlights
A long-standing model of cancer evolution is that tumor cells progress through stages via a reiterative process of expansion, genetic diversification by somatic mutation, and positive selection of subclones containing specific mutations.[1]
We show that the majority of Chronic lymphocytic leukemia (CLL) cases display-limited genetic change during that time interval, but that recurrent epigenetic changes at memory B-cell-specific polycomb repressive complex 2 (PRC2) targets are associated with disease progression
We identified somatic point mutations through whole-exome sequencing of matched germline and leukemia cell samples at both clinical time points
Summary
A long-standing model of cancer evolution is that tumor cells progress through stages via a reiterative process of expansion, genetic diversification by somatic mutation, and positive selection of subclones containing specific mutations.[1]. These studies examined fewer longitudinal CLL samples without intervening treatment, they observed that clonal evolution is less common before treatment,[3,5] which is consistent with the results of larger-scale CLL array profiling studies.[6]
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