Aberrant DNA Methylation and Genome Instability and Mutation in Cancer  

Li  S. , Wen  Y.H. , Wei  Y.J. , Wang  Y.H. , Liu  H.B.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
Author    Correspondence author
Cancer Genetics and Epigenetics, 2015, Vol. 3, No. 14   doi: 10.5376/cge.2015.03.00014
Received: 02 Oct., 2015    Accepted: 13 Nov., 2015    Published: 08 Dec., 2015
© 2015 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article:

Li S., Wen Y.H., Wei Y.J., Wang Y.H., and Liu H.B., 2015, Aberrant DNA methylation and genome instability and mutation in cancer, Vol.3, No.14, 1-5 (doi: 10.5376/cge.2015.03.00014)



In the process of normal cells transforming into cancer cells with the disruption control of epigenetic and genetic, they will gradually acquire the cancer Hallmarks. Epigenetic and genetic influence each other and closely cooperate to promoter oncogenic transformation in variety ways. It is clear that DNA methylation plays important roles in generation of mutation of tumor suppressor genes (TSGs) eventually lead to inactivation such as the probability of C mutation to T of the well-known TSGs p53 is high due to 5-methylcytosine residues is more prone to spontaneous deamination. The most common pattern of epigenetic control of tumor suppressor genes inactivation is hypermethylation of promoter region in cancers and the hypermethylation of CpG islands can also contribute to the increasing mutation rate of tumor suppressor genes such as CpG islands hypermethylation appeared to be tightly linked with the V600E mutation of the BRAF oncogene in colorectal cancer. Global hypomethylation is closely associated with chromosomal instability, which the methylation status of LINE-1 is a marker of global methylation, there is a significant relationship between LINE-1 hypomethylation and DNA copy number variation in the gastrointestinal stromal tumor. Aberrant DNA methylation is pervasive in cancer, which is similar to genomic instability and mutation.

Hypermethylation; Hypomethylation; Chromosomal instability; Mutation; Cancer

1 Introduction
In the successful disruption of cell proliferation, and angiogenesis, cell death, invasion and metastasis of the control, the normal cells will gradually turn into cancer cells (Hanahan and Weinberg, 2011). This process of evolution is the need to continue to accumulate carcinogenic characteristics in the clonal cell line and most importantly genetic mechanisms such as mutation, copy number variation, insertion, deletion, and recombination are consistent with the changes in the phenotype of the tumor. For this reason, cancer is considered to be a genetic disease for a long time (Choi and Lee, 2013; Esteller and Herman, 2002). However, the probability of occurrence of these genetic events is very low, so it is not a particularly effective method for malignant tumors, the epigenetic control mechanisms provide another option for obtaining stable oncogenic characteristics. Epigenetic states are flexible and varied in the process of cell differentiation, but they are important in determining the phenotype of cells. With the ongoing genetic and epigenetic studies, we know that they will interact with each other and work together to help the cells acquire cancer Hallmarks.

DNA methylation is a heritable but irreversible epigenetic modification, which has the potential to change the gene expression and has the profound development and the genetic influence (Jones and Baylin, 2002). Methylation can induce mutation, methylated cytosine normally occurs the probability of mutation of 10 to 40 times higher compared with unmethylated (Jones and Gonzalgo, 1997; Esteller and Herman, 2002; Rideout et al., 1990). Methylation has a prominent contribution to the generation of biological diversity and the germ-line mutation and to transition mutation which leads to tumor suppressor gene inactivation. In addition to mutations, tumor suppressor gene can also inactivated by high methylation level of promoter. The change of DNA methylation is a common feature of cancer and plays a driver role in the tumor primary formation process, this view has been confirmed by a lot of studies (Chen et al., 2015; Kok-Sin et al., 2015). The roles of 5-methylcytosine in cancer is specifically manifested in the following three aspects.

2 Methylation and Mutation
Methylation can induce tumor suppressor genes mutation. Methylated and unmethylated cytosine both undergo spontaneously hydrolytic deamination but the product is not the same, uracil and thymine respectively. Uracil bases is not inherent in DNA, compared with guanine thymine mismatch is easier to be repaired (Stier and Kiss, 2013; Song et al., 2011; Cooper et al., 2010). The difference products in deamination can be very good explanation of methylated cytosine relative to unmethylated cytosine was greater for the contribution of mutations. Therefore, in CpG dinucleotides the rate of methylated cytosine to thymine mutation probability is about ten times higher than the human genome other SNV (Hodgkinson and Eyre-Walker, 2011). This effect is particularly prominent in highly proliferative tissues because in the parent strand 5-methylcytosine deamination is occurring in DNA replication before, all the T will be a replacement with A so it will not be considered a kind of injury and repair. In human cancers, close to 1/4 TP53 mutation are caused by methylation. Although CpG dinucleotides in the human genome accounted for only 1% of all the dinucleotide, CpG dinucleotides occur transition mutations accounted for 25% of 254 point mutation in p53 gene in a study and in another study accounted for 33 percent of 324 p53 mutation. In other relevant p53 mutation research such as in 263 cases of human lung cancer with 7%, in 119 cases of HCC with 10% and in 180 cases of colorectal cancer with 41% were found in the dinucleotide CpG transition mutation. Rideout and coworkers showed that cytosine residues in the p53 gene known to have undergone somatic mutation were methylated in all normal human tissues analyzed (Rideout et al., 1990; Fortes et al., 2015).

Effect of cytosine methylation in germ cell lines also has been studied. The results of a study showed that human genetic diseases of 135 point mutation in 52 were occurred in CpG dinucleotides (37%). In an analysis of 216 mutations in the coagulation factor IX gene, giving rise to hemophilia B, 97 mutations were CpG transitions (45%). The prominent contribution of CpG dinucleotide in mutation was also obvious for germ-line mutations in tumor suppressor genes. The results of several LiFraumeni syndrome researches showed that 2 out of 6 germ-line mutations in the P53 gene were CpG transition mutations (Hensel et al., 1991). Three out of eight germ-line mutations in patients with retinoblastoma were found to be CpG transition mutations (Sasa et al., 1993).

In addition to the above mentioned, we also know that CIMP is associated with gene mutation. So what does CIMP means? Aberrant DNA methylation of promoter CpG islands was initially viewed as a stochastic genome event. However, CpG island hypermethylation was found in many cases of colorectal cancers with an exceptionally high frequency. Thus, CpG islands hypermethylation possibly attributed to out of epigenetic control. This phenomenon is considered as “CpG Island Methylator Phenotype” (CIMP) (Shen and Laird, 2013). So far, many studies have shown that CIMP is closely related to the gene mutation. For example, CIMP appeared to be tightly linked with the V600E mutation of the BRAF oncogene in colorectal cancer (Weisenberger et al., 2006), while CIMP was closely related with IDH1 mutation out of expectation in glioma (Noushmehr et al., 2010).

To sum up, we can see that DNA methylation can induce gene mutations in many ways, which can cause diseases and even cancer. In the process of cancer evolution and progression, the genetic and epigenetic mechanisms should be mutual influence, and ultimately cooperate with each other to obtain various cancer Hallmarks.

3 Aberrant Methylation and Alerting Gene Expression
In cancer, we can often see the changes in the two DNA methylation patterns: hypermethylation of promoter of tumor suppressor genes and the global hypomethylation. And then affect the expression of cancer genes to help cancer cells to obtain the selective advantage, therefore the DNA methylation pattern changes plays an important role in the process of malignant tumor formation (Laird, 2010).

Hypermethylation of promoter region is an important mechanism for gene silencing. The promoter region of cancer suppressor genes is typically low methylation in normal tissues and cells, while is hypermethylation in cancers. The hypermethylation of CpG islands is found in almost all cancers. Many of the cellular pathways are inactivated by the effects of this epigenetic change: DNA repair (hMLH1, MGMT), cell cycle (p14, p15, p16), cell apoptosis (DAPK), cell adhesion (CDH1, CDH13), detoxification (GSTP1) (Choi and Lee, 2013). Hypermethylation is not an independent branch of epigenetic control. It is closely related to other parts, such as methyl-binding proteins, DNA methyltransferases and histone deacetylase.

In addition to hypermethylation of promoter of tumor suppressor genes, there are a large number of literature showed that the global and gene specific loss of methylation have been observed in cancer. There is now an important question that hypermethylation of promoter region can inhibit the expression of genes, and whether or not the low methylation of specific pro-growth genes will increase their expression in cancers. A lot of works focused on DNA hypomethylation in cancer but unfortunately most of them have not analyzed the relation between the oncogenes expression level and their promoter region hypomethylation. Because there are a large majority of the cytosine located in repeated sequences, mainly the transposons. The global hypomethylation induced by repeated sequences demethylation in cancer has a close relationship with the mutation and genome instability (Easwaran and Baylin, 2013). We will discuss this issue in detail later.

We can see a great difference in the pattern of methylation in cancer and normal tissues. Differentially methylated regions (DMRs) play critical roles in development, aging and diseases. With the development of the next generation sequencing technology, the resolution of human genome methylation spectrum will be increasingly higher, but the price of sequencing will decrease very fast. Advances in technology have provided a great convenience for the study of the difference methylation pattern between cancer and normal tissues, but it has also brought a huge challenge to the data analysis. As a result, more and more highly effective and accurate bioinformatics tools and methods have been developed. For example, CpG_MPs: identification of CpG methylation patterns of genomic regions from high-throughput bisulfite sequencing data (Su et al., 2013); QDMR: a quantitative method for identification of differentially methylated regions by entropy (Zhang et al., 2011). With so many people’s efforts, we believe that more secrets hidden in DNA methylation will slowly be revealed.

4 DNA Methylation and Genomic Instability
It is worth noting that global hypomethylation is closely related to the genetic instability mentioned above, which implies that the abnormal methylation status in cancer cells plays an important role in the process of chromosome deviation.

A lot of studies have confirmed that global DNA hypomethylation can increase the instability of the chromosome and is very important in cancer. The methylation status of the long interspersed nuclear element-1 (LINE-1) sequence is a marker of global methylation. The methylation level of LINE-1 is lower than that of normal mucosa and is significantly correlated with lymph node metastasis, and the frequency of p53 mutation in esophageal squamous carcinoma cells (Kawano et al., 2014). Hiroyuki Kawano and coworkers point out that the whole genome hypomethylation caused by chronic inflammation, which initiate carcinogenesis of esophageal squamous cell carcinoma through chromosome instability. In addition, another team has been investigated the relationship between LINE-1 hypomethylation and chromosome abnormalities in the gastrointestinal stromal tumor (GISTs) (Igarashi et al., 2010). By carrying out an array CGH analysis they wanted to know whether LINE-1 hypomethylation is linked with chromosomal gain or loss. The results showed that chromosomal abnormalities associated with LINE-1 hypomethylation are often represented as losses, not gains and suggested a significant relationship between LINE-1 hypomethylation and DNA copy number variation in GISTs. Cristian Coarfa’s group have developed several tools such as Breakout, an algorithm for fast and accurate detection of structural variants, to investigate the interaction between hypomethylation and structural genomic variants. They demonstrated some previous findings that hypomehlation of DNA and binding sites of Suz12 are closely associated with genome instability in human germline. Their results suggested that structural mutations are not randomly distributed relative to the epigenome and are af4fected by the cell-type specific hypomethylation patterns in both somatic cells and germline.

The veil of hypomethylation affecting human genome stability has been revealed. With the development of the sequencing technology and analysis methods and tools, the secrets of interaction and mechanism between epigenome and structural genomic variation will gradually emerge from the water.

5 Conclusion
More and more researches confirmed that the mechanism of genetic and epigenetic influence each other and cooperate to promoter oncogenic transformation in a variety of ways. The cancer genome and epigenome affect and cooperate with each other to achieve similar results, such as the inactivation of tumor suppressor genes mentioned above such as p53, BRAF, IDH1, RB by either mutation or hypermethylation of promoter regions. On the one hand, global DNA hypomethylation can induce human genomic instability, which gives a more chance for the mutation of the oncogene, the methylation status of LINE-1 is closely associated with chromosomal stability. On the other hand, hypermehtylation can increase the mutation rate of tumor suppressor genes such as hypermethylation of promoter region produced a favorable condition for inactivation mutant of the BRAF in the colorectal cancer.

Many questions remind in this field such as altered methylation patterns in cancer cell genomes: Cause or consequence? There is such a point that DNA methylation is considered as a consolidating rather than an initiating event in tumor suppressor gene inactivation. Somatic inactivation of X chromosome in female, where DNA hypermethylation of promoter CpG islands is after inactivation not before (71, 95, 108). Another major question is how to investigate the mechanistic basis for well-known examples of disruption of epigenetic control. Therefore, the identification of epigenetic drivers must rely more on the analysis of transcriptional consequences and most importantly functional experimental validation of the effect of epigenetic genes inactivation on cellular proliferation, immortality, angiogenesis, cell death, invasion and metastasis affected.

This work was supported by National Natural Science Foundation of China (grants 61403112, 31371334).

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