DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors

Abstract

Summary The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Analysis of ITH in gliomas (Mazor et al, 2015) as well as prostate cancers (Aryee et al, 2013) and esophageal squamous cell carcinomas (Hao et al, 2016) has suggested that the extent of ITH calculated from DNA methylation mirrors ITH measures captured at the genomic level.…”

Overcoming therapeutic resistance in glioblastoma: the way forward

“…Segregating clones based on the presence of independent or shared mutations has revealed part of the tumor development process (27)(28)(29)(35)(36)(37). The clonal evolution model posits that tumor formation is initiated in a cell of origin and is followed by the accumulation of single or multiple somatic genetic alterations, leading to advantages in survival or growth (38).…”

“…The fittest cell populations likely establish precancerous clones, although we have little direct evidence to support this process in human GBM because of limitations in detecting the early steps in brain cell transformation (42,43). Divergent genetic alterations in early transformed cells can subsequently give rise to a variety of clones under the selective pressure of the evolutionary ecosystem in the tumor (27)(28)(29)(35)(36)(37). A cell's spatial location in the tumor is related to its divergent genomic profile, and clones with similar types of genetic alterations are more proximal to each other than those with dissimilar profiles (Figure 1B and refs.…”

“…Surgical debulking reduces intratumoral heterogeneity by removing many subclones from the tumor. This conclusion is based on two observations: first, there is regional diversity in primary tumor clones, suggesting limited cell mixing (27-29, 36, 37, 44), and second, comparison of primary/ recurrent tumors of patients having only received surgery shows that the recurrences diverge early from the primary tumor and lack the end mutations found in the primary tumor (27,36). Postoperative chemo-and radiotherapies can likely also reduce clonal diversity when only biopsy or partial surgical resection is possible, (106), and ID1 (107).…”

Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma

“…20,21 For instance, patients with IDH mutation showed hypermethylation of the CpG island and increased histone demethylation. [22][23][24] IDH converts isocitrate to a-ketoglutarate (a-KG) during normal TCA cycle, whereas mutant IDH converts a-KG to D-2-hydroxyglutarate (D-2HG) in an NADPH-dependent manner that has been associated with secondary GBM. [22][23][24][25][26] Nonetheless, 4 independent cases of MRI-classified SVZassociated GBM used in this study do not contain IDH mutation (Fig.…”