DNA Methylation and Cancer

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International Journal of Medicine Papers 2016; 1: 6–8
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DNA methylation and cancer; A Review Article
Maruf Raza A.K.M.1
*
1. Assistant Professor of Pathology, Jahurul Islam Medical College, Kishoregonj, Bangladesh.
Abstract
Epigenetics is the study of the changes in gene expression that are heritable and do not involve a change in the DNA sequence.
DNA methylation is one of the key epigenetic mechanisms that is clearly understood. DNA methylation is the process that add
methyl group to the 5th
carbon atom of the cytosine base at CpG dinucleotides without changing the nucleotide sequence.
Transcriptional silencing in X inactivation and genomic imprinting are two important epigenetic mechanisms where DNA
methylation plays a major role. It is well known that DNA hypermethylation and hypomethylation are directly associated with
tumor formation. Hypomethylation leads to the inappropriate and increased levels of gene expression in tumors. Trancriptional
repression that is seen in cancers is also mostly due to hypermethylation. DNA methylation plays a major role in transcriptional
silencing in X inactivation, genomic imprinting and tumor or cancer formation. Changes in the pattern of DNA methylation have
been a consistent finding in cancer cells. DNA methylation plays an important role in the generation of mutations in human tumors.
The high incidence of C-to-T transitions found in the p53 tumor-suppressor gene. DNA methylation plays a crucial role in the
regulation of gene expression and chromatin organization within normal eukaryotic cells. In cancer patterns of DNA methylation
are altered with global hypomethylation and hypermethylation of a subset of CpG-dense gene-associated regions (CpG islands).
Key words: Epigenetics, DNA methylation, Cancer
1. Introduction
Cancer is essentially a genetic and environmental disease arising from a series of germ-line and/ or somatic DNA
changes. DNA methylation is the process that add methyl group to the 5th
carbon atom of the cytosine base at CpG
dinucleotides without changing the nucleotide sequence. Transcriptional silencing in X inactivation and genomic
imprinting are two important epigenetic mechanisms where DNA methylation plays a major role. It is well known
that DNA hypermethylation and hypomethylation are directly associated with tumor formation. Hypomethylation
leads to the inappropriate and increased levels of gene expression in tumors. Trancriptional repression that is seen in
cancers is also mostly due to hypermethylation (1). DNA methylation involves a modification of DNA and has been
found to influence a variety of processes that affect DNA integrity and function. It has therefore long been speculated
that DNA methylation might play a role in the onset of cancer. In the past decade a solid foundation for this view has
been laid by a series of reports documenting various changes in the DNA methylation patterns in transformed cells in
vitro and in vivo. DNA methylation plays an essential role in normal development through its effects on gene
imprinting, X-chromosome inactivation, and transcriptional silencing of repetitive elements (2). In the Human
Genome, most of the 5-methylcytosines occur in CpG dinucleotides. DNA methylation is carried out by DNA
methyltransferases (DNMTs) - DNMT1, DNMT3A and DNMT3B (3).
2. Biological Significance of DNA Methylation
It is nearly 15 years since scientists recognized the significance of DNA methylation in tumors. Studies have shown
* Corresponding author. Tel.: +8801711306123
E-mail address: drmarufraza@gmail.com
Citation to This Article: Maruf Raza AKM. DNA methylation and cancer; A Review. International Journal of Medicine Papers 2016; 1: 6–8

2. Maruf Raza A.K.M. International Journal of Medicine Papers 2016; 1: 6–8
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that methylation patterns in tumor cells are significantly different from those in normal cells (4). Tumor cells may
even display hypomethylation in genomic DNA even before tumor formation which leads to increased and
inappropriate gene expression (5). Hypermethylation of CpG islands is the most commonly observed alteration in
DNA methylation in cancers. Transcriptional repression due to hypermethylation of promoters of tumor suppressor
genes is identified as one of the couses of tumor formation. In colorectal, lung and breast carcinomas, cell cycle
inhibitor P16
INK4a
is heavily hypermethylated (6). Hypermethylation profiling over more than 15 tumor types (colon,
stomach, pancreas, liver, kidney, lung, head and neck, breast, ovary, endometrium, kidney, bladder, brain, and
leukemia and lymphomas) has shown that all the metabolic pathways are affected by promoter hypermethylation-
associated silencing (3).
3. DNA Methylation in Mammals
DNA methylation in mammals is found as a covalent modification at the fifth carbon position of cytosine residues
within CpG dinucleotides. Most of the CpG dinucleotides in the human genome are methylated. CpG islands are about
1 kb long and are not only CpG-rich, but generally G/C-rich as well and are found at the 5' end of genes (7). All known
housekeeping genes and some tissue-specific genes have associated CpG islands. However, 5-methylcytosine makes
up less than 1% of all nucleotides and CpG dinucleotides and 5-methylcytosine are unevenly distributed in the genome.
Most of the genome is heavily methylated with a corresponding deficit in CpG dinucleotides (8).
4. Changes in the DNA Methylation Pattern in Cancer Cells
Changes in methylation levels as well as modifications of methylation patterns of individual genes have been seen as
a characteristic trait in a great variety of tumor cells. These findings, however, have not lead to simple conclusions
regarding the role of methylation in carcinogenesis, since both DNA hypomethylation and hypermethylation have
been associated with cancer in numerous investigations (9).
5. Hypomethylation
Reduced levels of global DNA methylation have been reported for a variety of malignancies in the past decade (9).
Gama Sosa and coworkers found that in a wide variety of tumors, hypomethylation not only correlated with tumour
transformation, but also with tumor progression and suggested an early role for DNA hypomethylation in colorectal
cancer (3). Hypomethylation of proto-oncogenes has been observed particularly in liver tumors and leukemias. A
variety of proto-oncogenes, such as the c-fos gene, the c-myc gene and the Ha-ras and Ki-ras genes have shown
reduced levels of DNA methylation in liver tumors. Other examples of proto-oncogenes being hypomethylated in
various human leukemias include the Erb-A1 gene and the bcl-2 gene (9).
6. Hypermethylation
There have also been many reports of regional increases in DNA methylation levels. Baylin and coworkers have found
regional hypermethylation on chromosomes 3p, 11p and 17p in a variety of human tumors. These include CpG island
areas that are normally never methylated in vivo, but are found to be methylated in tumor tissues (9).
There is evidence for inactivation of tumor-suppressor gene function through hypermethylation of the Rb gene in
sporadic retinoblastoma. It is possible, therefore, that hypermethylation of tumor-suppressor genes leading to gene
inactivation results in a selective growth advantage of the transformed cells (10).
7. Significance of DNA methylation changes in carcinogenesis
Changes in DNA methylation consisting of either DNA hypomethylation or hypermethylation are commonly seen in
cancer cells. The significance of these alterations in the genesis of cancer is an ongoing research. The crucial question
is whether hypomethylation of specific growth-promoting genes such as proto-oncogenes or the hypermethylation of
growth-suppressing genes such as tumor-supressor genes contributes to a selective advantage of the cancer cell and
therefore may represent one of the steps in the sequence of events leading to malignancy (9). Hypermethylation of
tumor suppressor genes might indeed be involved in maintaining transcriptional repression and thus might provide a
selective growth advantage (3).

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8. Clinical Applications of DNA Methylation
Recent advances in our understanding of cancer-associated DNA methylation underlie many promising clinical
applications including the development of molecular markers for early detection of cancer, prediction of prognosis
and prediction of treatment outcomes. Current genome-wide methylation profiling technology which permits the rapid
and simultaneous analysis of thousands of loci will likely help identify novel, superior methylation markers with
higher sensitivity and specificity (2). Combinations of multiple methylation markers may provide even more
prognostic potential. Since genes involved in the repair of DNA damage are frequently targeted by hypermethylation
in cancers, the study of these loci may be useful in predicting response to chemotherapy (3).
9. Summary
Epigenetics is the “study of the changes in gene expression that are mitotically and/or meiotically heritable and do not
involve a change in the DNA sequence”11. DNA methylation is the process that add methyl group to the 5th
carbon
atom of the cytosine base at CpG dinucleotides without changing the nucleotide sequence is one of the key processes
in epigenetic mechanisms. Transcriptional silencing in X inactivation and genomic imprinting are two important
epigenetic mechanisms where DNA methylation plays a major role. It is well known that DNA hypermethylation and
hypomethylation are directly associated with tumor formation. Hypomethylation leads to the inappropriate and
increased levels of gene expression in tumors. Trancriptional repression that is seen in cancers is also mostly due to
hypermethylation.
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