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 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.

Perturbation of the normal immune system in patients with CLL

“…24 This observation merits further investigation and it appears possible that epigenetic programming is an additional important determinant that links B-cell signaling with IL-10 production (Samantha Drennan, Chris Oakes, and F.F., manuscript in preparation). 90 Although T cell help is important in the differentiation of B10pro cells into effector B10 cells, 89 CLL cells resemble anergic B cells operating in a T cellindependent fashion, suggesting that classical cognate T cell help is unlikely to contribute. 6 One important factor may be BAFF, which is also expressed on monocytes/macrophages within proliferating centers and promotes B-cell activation, proliferation, and IL-10 production.…”

Chronic lymphocytic leukemia: Time to go past genomics?

“…DNA methylation has been compared between normal B-cell populations and CLL [136][137][138][139], leading to important observations. In a first report, three CLL classes were defined, based on DNA methylation patterns, which relate to naive B cells, memory B cells, and the third group being intermediate.…”

“…However, methylation disorder is associated with prognosis: the more disorder, the poorer outcome [138]. The reasons underlying the methylation disorder are not known, but there seems to be an association with gene mutations: increasing methylation heterogeneity is associated with an increasingly complex subclonal genetic architecture [139].…”

Dynamic evolution of clonal epialleles revealed by methclone

“…Epipolymorphism has been used to measure epigenetic heterogeneity [22], but it does not represent the epiallelic shift between samples. For each loci, the epipolymorphism e ¼ 1− …”