Cancer Genetics and Epigenetics 2015, Vol.3, No.14, 1-5
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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 thi s
epigenetic change: DNA repair (hMLH1, MGMT),
