Abstract
BACKGROUND: The clonal evolution of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast, tumor epigenetic states are reversible and sensitive to the tumor microenvironment, presumably precluding the use of epigenetics to discover the clonal and sub-clonal evolution of tumors. We recently used mutation patterns to learn how low grade gliomas evolve over time, and also discovered that temozolomide treatment of LGG is associated with TMZ-induced hypermutation and malignant progression to GBM (BE Johnson et al, Science, 2014). METHODS: We used exome and RNA sequencing, DNA methylation arrays, along with computational analysis to construct phylogenetic and phyloepigenetic relationships among co-evolving tumor cell populations. RESULTS: Here we examined the spatial and temporal dynamics of DNA methylation in our clinically and genetically characterized cohort of IDH1-mutant low-grade gliomas and their patient-matched recurrences. While all tumors exhibited the hypermethylation signature associated with IDH1 mutation, low-grade gliomas that underwent spontaneous or temozolomide-associated malignant progression to high-grade glioblastoma multiforme (GBM) had a unique signature of DNA hypomethylation enriched for both active enhancers, and sites of age-related hypermethylation in the brain. Genes with promoter hypomethylation and concordant transcriptional upregulation during evolution to GBM were enriched in cell cycle function, evolving in concert with genetic alterations that deregulate the G1/S cell cycle checkpoint. Despite the plasticity of tumor epigenetic states, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations in the same patients. CONCLUSIONS: These findings highlight widespread co-dependency of genetic and epigenetic events throughout the clonal evolution of initial and recurrent gliomas.