The role of epigenetics in cancer heterogeneity

By Milena Flankova

Abstract

Epigenetics in the context of cancer is still poorly explored. In the last two decades it has become apparent that cancer cells within a tumour may have distinctive genetic and epigenetic features which can be affected by anticancer treatments negatively or positively. This article summarises present knowledge on the role of the epigenome in tumourigenesis and subsequent growth, as well as discussing the links between genetics and epigenetics in cancer.

Introduction

Tumourigenesis is often driven by both genetic and epigenetic abnormalities. Genetics is a field concerned with a genetic code and its variation within and across individuals. In cancer genetics, “passenger” genes tend to be epigenetically silenced and do not induce tumourigenesis, whereas “driver” genes are the ones responsible for causing cancer, specifically for initiating clonal expansion. These genes might harbour various genetic mutations or more frequently, they can be acted upon by epigenetic mechanisms (Kelly, de Carvalho and Jones, 2010a).   

Epigenetics is the study of the interplay between genes and gene products that act upon them. Epigenetic marks on DNA are tightly associated with the environment and stochasticity affecting the genetic sequence over time. Gene expression can be regulated via altering chromatin exposure by epigenetic mechanisms such as DNA methylation and histone modifications. Cancers tend to have disrupted methylation patterns in a gene promoter region which are correlated with inactivation of a gene function and targets tumour-suppressor, cell cycle and DNA-repair genes among many others (Baylin and Herman, 2000; You and Jones, 2012).A common misconception is that cancer arises due to a mutation in one of the “driver” genes and that all cancer cells are the same. Even though tumorigenesis is considered to be a clonal process developing from a single malignant cell, resulting daughter cells can have distinct characteristics. The clonal evolution of tumour cells was first described by Peter C. Nowell in 1976 (Nowell, 1976). Cancer heterogeneity confers molecular and phenotypic variations  either within the tumour, which is called intratumoural heterogeneity, or in different patients that have the same tumour subtype, which is referred to as intertumoural heterogeneity (Jamal-Hanjani et al., 2015a). Interpatient tumoural heterogeneity may occur due to various patient-specific factors such as different somatic mutations, genetic variations in the germline and tumour microenvironment where various resident and infiltrating host cells are involved in interactions with heterogeneous cancer cells. Intratumoural heterogeneity, which is a consequence of genetic instability, is more complex in its nature and can be described as spatial or temporal. Spatial heterogeneity represents an irregular distribution of subclones which are mutated clones across different or within the same metastatic site in a single patient. Temporal heterogeneity, on the other hand, refers to differences in molecular features occurring at a single disease site over time as a consequence of the natural development of the disease or medical interventions (Dagogo-Jack and Shaw, 2018). These concepts are illustrated in Figure 1.

Figure 1. Spatial and temporal heterogeneity of tumours (Dagogo-Jack and Shaw, 2018). 

Cancer heterogeneity is linked to enhanced disease severity, recurrence, implying the reestablishment of cancer in the same or different tissues after treatment, and low survival levels in case of progressive metastasis. Intratumoural heterogeneity is thought to pose great challenges for developing universal molecular targeted therapeutics that would be effective against a sufficiently large set of cancer cells. Apart from intrinsic drug resistance that arises due to heterogeneity, resistance to cancer therapeutics acquired during or soon after a treatment has been already proven (Li et al., 2008; Ramirez et al., 2016) and is schematically depicted in Figure 2.

Figure 2. Intratumoural heterogeneity and resistance to anticancer treatment (Dagogo-Jack and Shaw, 2018). Primary tumours are exposed to different selective pressures (e.g. chemotherapy, hypoxia, infiltrating stromal and immune cells). (A) represents subclones that possess intrinsic resistance and (B) demonstrated subclones that previously were non-resistant “persister” cancer cells with tolerance acquired through somatic alterations after exposure to selective pressure. The remaining subclones/clones (blue) are eliminated by selective pressures as these cancer cells do not possess any corresponding resistance mechanisms. Resistant subclones (green and red), on the other hand, multiply, evolve and can even metastasise (Jamal-Hanjani et al., 2015b; Dagogo-Jack and Shaw, 2018).

Epigenetic alterations in cancer and the field defect

Epigenetic changes in cancer can be followed through the chromatin landscape comprising of histone modifications which include acetylation, ubiquitylation, sumoylation, phosphorylation and methylation of DNA, and alterations in chromatin conformation (Park and Han, 2019).

In human cancers, an anomalous pattern of epigenetic makeup is more common than gene mutations. For instance, epigenetic silencing of well-known driver genes CDK2NA and MLH1 occurs more frequently than mutational inactivation of these genes (Beggs et al., 2013). In fact, epigenetic changes frequently dictate gene mutations and genomic instability in cancer. This was observed when DNA repair genes such as CHRF, MLH1, MGMT, FANCF and others were epigenetically silenced (Toyota and Suzuki, 2010). Epigenetic variations causing cellular plasticity which is inactivation of genes linked to the previous cell type and activation of the ones characteristic of a new cell type, drive phenotypic heterogeneity in cancers. Such plasticity helps to tolerate any incoming environmental stress during tumour progression. Cancer cells with significant plasticity are thought of as “cancer stem cells” because these cells represent a weakly proliferative and drug-resistant subpopulation (Chisholm et al., 2015; Pisco and Huang, 2015).

Atypical distribution of epigenetic marks may act as an indicator of a “field defect” or “field cancerization” which implies the acquisition of malignant mutations that do not result in a change in tissue morphology, yet promote tumorigenesis. The field defect tends to be associated with elevated numbers of epigenetic modifications, one of which is methylation (Bernstein, 2013). In DNA, adenine and cytosine can be methylated. However, in eukaryotes, cytosine is usually the only methylation site. In the case of cytosine methylation, a methyl group is covalently attached to the fifth carbon on the carbon ring of cytosine, producing 5-methylcytosine (5mC) (Brero, Leonhardt and Cardoso, 2006). For instance, methylation in promoter regions of RASSF1A, p16, MGMT etc. leads to no phenotypic variation of mucosa in colorectal cancer patients. Even though these epigenetic alterations do not cause phenotypic transformations, they can be found in an early tumour still in its primary site and a surrounding area after tumour resection. Such changes in epigenetic makeup occur relatively early on in cancer development (Guo et al., 2004) and can be used as potential biomarkers in cancer diagnostics.

Ubiquitous DNA hypomethylation within the whole genome and occasional hypermethylation are commonly observed in cancer. Hypomethylation of typically methylated promoter regions is associated with enhanced transcription. However, methyl group removal can be also observed in gene bodies and in flanking regions of genes, leading to downregulated gene expression (Berman et al., 2011). This was evidenced using mice with a non-functional DNA methyltransferase 1 allele. The mice developed severe T-cell lymphomas, thus highlighting  the importance of hypomethylation in tumour formation (Gaudet et al., 2003).

Genetics is tightly related to epigenetics and this interconnection persists in cancers. It has been shown that CpG islands are a target for DNA hypermethylation (Jones and Baylin, 2007). CpG islands are DNA stretches that have high numbers of CG nucleotide repeats and are located in the promoter region of eukaryotic DNA. They are usually unmethylated in comparison to other CpG regions within the genome that exhibit 60 to 90 % methylation (Brero, Leonhardt and Cardoso, 2006). In tumours, CpG islands tend to be hypermethylated. Previous research has shown that genetic mutations may induce epigenetic changes; a mutation in the isocitrate dehydrogenase gene (IDH1) in glioma causes a CpG island methylator phenotype (CIMP) through epigenome remodelling, specifically through DNA hypermethylation (Turcan et al., 2012). Similarly, a mutation in BRAF can be acquired in response to DNA hypermethylation in tumours bearing CIMP (Hinoue et al., 2009).

Clonal evolution

In a heterogenous tumour, cancer cells can be different in their genetic and epigenetic makeup enhancing the potential for tumour propagation. A clone dominant in the tumour is not always the one that directs tumour development and determines malignant potential (Jamal-Hanjani et al., 2015b). Next-generation sequencing has shown that malignant tumours have the same clonal origins established in early cancer development. However, mutations that arise further in cancer progression belong to subclones which are the minority within the tumour (Burrell et al., 2013). Subclones tend to have intrinsic or acquired resistance to cytotoxic and targeted therapies (Engelman and Settleman, 2008; Misale et al., 2012). Despite lacking a fitness advantage, these cancer cells carry driver mutations that tend to be non-cell autonomous, meaning that a gene product indirectly participates in signal transduction. This is an independent risk factor that allows subclones to lead phenotypic variation within the tumour and disease progression (Marusyk et al., 2014). Moreover, the initial and recurrent tumours tend to have a few of the same non-coding somatic mutations suggesting that the recurrent tumour does not develop independently of the original one. Figure 3 illustrates that this phenomenon is likely to be attributable to minor and dormant cancer cells such as subclones because they can become the main driving force of tumour growth after treatment (Johnson et al., 2014a).

In spite of clonal evolution, phenotypic convergence within and across types of tumour persists. This implies that genetic traits involved in resistance to therapy and disease development target a limited number of signalling pathways and hence can be potentially detected by drugs (Johnson et al., 2014b). Phylogenetic trees based on the distance in the evolutionary timeline can be constructed for clonal and subclonal cancer cells. This would aid in deciphering various consequent stages of the development of intratumoural heterogeneity which would provide insights for personalised targeted cancer treatments. Clonal driver mutations are found within the evolutionary tree’s “trunk”, whereas subclonal driver mutations which are present in a subset of cancer cells are observed within the phylogenetic branch (Fig. 3) (Campbell et al., 2008).

Figure 3. Evolutionary tree constructed based on shared and unique mutational events in cells within a single tumour (Jamal-Hanjani et al., 2015b). (A) represents genetic mutations shared by all tumour cells and corresponds to a blue “trunk” of the evolutionary tree. (B) and (C) both represent cells with mutational events which arise later on in tumourigenesis (yellow branches). (D), (E) and (F) denote unique alterations that are present within a restricted region of the tumour and occur later in the evolutionary timeline (Jamal-Hanjani et al., 2015b).

Clonal architecture can be examined using parallel pyrosequencing which is one of the next-generation sequencing techniques. This method is focused on measuring the release of pyrophosphate in the process of joining an introduced dNTP to the DNA strand that is being synthesized. This way, subclones can be detected with relatively high sensitivity (such as 1 in 5000 copies) and for the construction of phylogenetic trees using clones and subclones in a tumour (Campbell et al., 2008). Research which aims to understand the clonal composition of breast cancers has utilised single nucleus sequencing (SNS) which involves parallel pyrosequencing. This approach includes flow-sorting for the isolation of nuclei based on separating differently fluorescent cells. SNS is preferred to affinity chromatography and other methods due to high sensitivity and negligible uncertainties caused by nonspecific adsorption (“Flow sorting”, 1988; Navin et al., 2011).

Historically, intratumoural heterogeneity and clonal evolution have been investigated primarily through genetic changes such as somatic mutations and copy-number alterations. However, tumours exhibiting genetic homogeneity can have a varied response to therapy due to differences in the epigenome. Therefore, this approach is not always representative of clonal evolution  (Kreso et al., 2013).

There are studies where the role of epigenetics in contributing to intratumoural heterogeneity has been analysed. Most of the research was done on DNA methylation as it is relatively easy to obtain genomic DNA and to quantify the results of DNA methylation assays (Sigalotti et al., 2004; Dawson and Kouzarides, 2012). Enzymatic regulators that direct epigenetic modifications can be divided into writers, erasers, readers and movers. Writers are enzymes that introduce DNA methylation and drive histone modifications. On the other hand, erasers are enzymes that take these marks off. Readers attach to modifications and promote epigenetic effects. Movers locate nucleosomes in the genome (Ahuja, Easwaran and Baylin, 2014). These regulators of the epigenome are typically mutated in cancer – once again highlighting the link between genetics and epigenetics (Shen and Laird, 2013; Mack et al., 2015).

DNA methylation patterns have been previously used to reflect the evolution of tumours (Brocks et al., 2014). Moreover, phyloepigenetic trees from the aberrant methylation levels in various CpG regions, are important in subclonal diversification of oesophageal squamous cell carcinoma (ESCC) tumours (Hao et al., 2016). Hence, changes in the epigenome can be also used as a reference for constructing evolutionary trees depicting the acquisition of heterogeneity within tumours. Investigating both genetic and epigenetic variation within one tumour by constructing evolutionary trees with a help of bioinformatics can provide insight into the interdependence of genetic and epigenetic events in cancer types, as well as into clonal and subclonal evolution. In fact, phyloepigenetic trees linking genetics with  epigenetics in the context of cancer have already been constructed. An example is an aforementioned study investigating hypermethylation and gene silencing in glioma (Mazor et al., 2015).

Novel anticancer epigenome-based treatments

As epigenetics has been shown to have a large impact on cancer progression, epigenetic modifications are good candidates for anticancer treatment, especially given that they are reversible (Kelly, de Carvalho and Jones, 2010b). Furthermore, epigenetic machinery is now being targeted for the development of epigenome-based personalised anticancer therapies (Salamero et al., 2020).

Acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and other malignancies are associated with epigenetic dysfunction which is manifested as inactivation of lysine-specific demethylase 1 (LSD1) and other epigenetic regulators (Gallipoli, Giotopoulos and Huntly, 2015; Feng et al., 2016; Ishikawa et al., 2017). LSD1 is a part of epigenetic machinery as it demethylates lysine residues on histone tails (Shi et al., 2004) and importantly, promoter regions (Fang et al., 2010; Li et al., 2012). LSD1 is targeted in carcinogenesis and later on, in cancer stem-like cells (Harris et al., 2012; Karakaidos, Verigos and Magklara, 2019). Therefore, there are various drugs in development that irreversibly inhibit LSD1, such as ORY-1001, TCP, ORY-2001, IMG-7289 etc (Fang, Liao and Yu, 2019).  Recently, a first-in-human Phase 1 clinical study was performed on Iadademstat (ORY-1001) and it was concluded that this drug is safe to use (Salamero et al., 2020).

Single-cell molecular analysis, sequential liquid biopsy and multiregion sequencing are now being used to investigate cells with specific molecular features within a heterogeneous tumour that initiate minimal residual disease whereby some leukaemic cells remain after treatment causing relapse. New single-cell proteomics techniques can be used for identifying proteins from individual cells and investigating gene expression and production of functional gene products at the same time. Liquid biopsies have the potential to detect subclonal populations with relatively high specificity and sensitivity, whereas multiregion sequencing detects differences in mutations and copy number variation between sites within a single tumour. Combined with bioinformatics, targetable cancer driver cells which are responsible for causing cancer recurrence can potentially be identified and eliminated by polytargeting therapies (Lim and Ma, 2019).

Apart from intratumoural heterogeneity and therapy-induced resistant subpopulations, pharmacokinetic factors including drug solubility, systemic distribution, metabolism and elimination can dictate the success of anticancer treatment (Holohan et al., 2013). 

Conclusion

Epigenetic alterations are important factors in tumour establishment and progression. To enhance the understanding of the role of the epigenome in cancer heterogeneity and in impairing drug efficiency, new methods should be developed for detecting changes in epigenetic marks besides methylation which include phosphorylation, acetylation and other modifications present on DNA or histones.

To date, most research has focused either on genetic mutations or methylation patterns in tumours and there is a limited number of studies that explore an interplay of genetics and epigenetics in cancers. Hence, to identify the mechanisms of resistance and to generate effective anticancer treatments which bypass intratumoural heterogeneity, the evolutionary history of clones and subclones within a tumour should be understood from both genetic and epigenetic perspectives. Furthermore, a strong emphasis should be placed on interactions of a tumour with its microenvironment, as well as on the effects of variability of tumour microenvironment on the progression of cancer. 

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