Abstract IA08: An epigenome perspective of human tumor evolution
Authors: Mazor Tali , Pankov Aleksandr , Song Jun , Costello Joseph 
Published: May 2016

Abstract
Cancers develop through a process of clonal evolution in which ongoing genetic and epigenetic diversification allows for repeated cycles of sub-clonal selection and expansion (Greaves and Maley, 2012; Nowell, 1976). As a result, human tumors can display substantial intratumoral heterogeneity, including discordant genetic alterations between the initial tumor and local recurrence or distant metastases (Gerlinger et al., 2012; Okosun et al., 2014; Wu et al., 2012; Yachida et al., 2010). As mutations accumulate over time, genomic profiling of spatially or temporally separated tumor samples can be used to reconstruct the evolutionary history and underlying clonal architectures of individual tumors (Gerlinger et al., 2014). In contrast to stable genetic events, epigenetic states are reversible and may change in response to the tumor microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny.
In low-grade glioma, the course of tumor evolution is particularly clinically significant. Low-grade gliomas are diffuse, infiltrative tumors that recur locally and may unpredictably undergo malignant progression to a higher grade with a worse prognosis (Sanai et al., 2011). Recurrences that progress to highly malignant WHO grade IV glioblastoma (GBM) acquire genetic alterations in the RB and AKT-mTOR pathways (Johnson et al., 2014; Louis, 2006). In fact, adjuvant treatment with alkylating chemotherapeutics such as temozolomide (TMZ) can induce hypermutation that emerges in recurrent tumors (Bodell et al, 2003; Hunter et al., 2006), and we recently linked treatment-associated driver mutations in these two pathways to malignant progression of grade II glioma to GBM (Johnson et al., 2014). The treatment associated malignant progression follows selection of tumor cells with epigenetic silencing of the DNA repair protein MGMT (van Thiujl et al, 2015).
The critical role that epigenetic alterations play in the development and therapeutic response of gliomas is increasingly being appreciated (Fouse and Costello, 2009). Somatic mutations in IDH1 or IDH2 may be the first genetic driver in the development of many low-grade gliomas (Johnson et al., 2014; Lai et al., 2011; Watanabe et al., 2009). Genetic mutations in IDH genes induce a pattern of early epigenetic alterations known as the glioma CpG island methylator phenotype (G-CIMP) characterized by extensive remodeling of the DNA methylome (Hill et al., 2014; Noushmehr et al., 2010; Toyota et al., 1999; Turcan et al., 2012). The inactivation of other genes mutated in low-grade gliomas, such as ATRX (Jiao et al., 2012) and SMARCA4 (Johnson et al., 2014), is known to induce specific DNA methylation changes as well (Banine et al., 2005; Gibbons et al., 2000). Although there has been extensive characterization of tumor methylomes using a single sampling per tumor, little is known about intratumoral heterogeneity at the epigenetic level or of temporal evolution of the low-grade glioma methylome and its relationship to the genome. In this presentation, I will show that phylogenic analysis of spatial and temporal patterns of either reversible DNA methylation or irreversible somatic mutations independently yield remarkably similar evolutionary histories. I will also incorporate this inter-dependent evolution into a detailed model of brain tumorigenesis that extends from the first mutation and epimutations through tumor recurrence.
Citation Format: Tali Mazor, Aleksandr Pankov, Jun Song, Joseph Costello. An epigenome perspective of human tumor evolution. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA08.