CpG island hypermethylation

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CpG island hypermethylation is a phenomenon that is important for the regulation of gene expression in cancer cells, as an epigenetic control aberration responsible for gene inactivation. Hypermethylation of CpG islands has been described in almost every type of tumor.

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Many important cellular pathways, such as DNA repair (hMLH1, for example), cell cycle (p14ARF), apoptosis (DAPK), and cell adherence (CDH1, CDH13), are inactivated by it. [1] Hypermethylation is linked to methyl-binding proteins, DNA methyltransferases and histone deacetylase, but the degree to which this process selectively silences tumor suppressor genes remains a research area. The list for hypermethylated genes is growing.

History

The first discovery of methylation in a CpG island of a tumor suppressor gene in humans was that of the Retinoblastoma (Rb) gene in 1989. [2] This was just a few years after the first oncogene mutation was discovered in a human primary tumor. The discovery of the methylation-associated inactivation of the Von Hippel-Lindau (VHL) gene revived the idea of the hypermethylation of the CpG island promoter being a mechanism to inactivate genes in cancer. [3] Cancer epigenetic silencing in its current state was born in the labs of Baylin and Jones, [3] where it was proven that CpG island hypermethylation was a common inactivation mechanism of the tumor suppressor gene p16INK4a. The introduction of methylation-specific PCR and sodium bisulfite modification added tools to the belt of cancer epigenetics research, [3] [4] and the list of candidate genes with aberrant methylation of their CpG islands has been growing since. [5] Initially, the presence of alterations in the profile of DNA methylation in cancer was seen as a global hypomethylation of the genome that would lead to massive overexpression of oncogenes with a normally hypermethylated CpG island. [6] Lately, this is considered as an incomplete scenario, despite the idea of the genome of the cancer cell undergoing a reduction of its 5-methylcytosine content when compared to its parent normal cell being correct. [5] In normal tissues, the vast majority of CpG islands are completely unmethylated with some exceptions. [1] The association of transcriptional silencing of tumor suppressor genes with hypermethylation is the foundation upon which this subset of cancer epigenetics stands.

An algorithm to find functional DNA methylation in cancer cells Algorithm.png
An algorithm to find functional DNA methylation in cancer cells

Structure

In a normal cell, the CpG island is hypomethylated, [7] and the rest of the genome is methylated. It is evident that the hypomethylation of the CpG island in normal cells provides no additional steric hindrance to future binding. The majority of CpG pairs in mammals are chemically modified by the covalent attachment of a methyl group to the C5 position of the cytosine ring. [8] This modification is distributed throughout the genome and represses transcription. A CpG island is a cytosine and guanine linked by a phosphate in a repeated sequence. These are genetic hotspots as they are sites for active methylation. The expression of a gene is tissue specific, which leads to variation in tissue function. Methylation of a gene prevents expression of a gene in a particular way.

Methylation of cytosine to 5- methylcytosine: DNA methylation is the addition of a methyl group to the DNA that happens at cytosine. The image shows a cytosine single ring base and a methyl group added on to the 5 carbon. In mammals, DNA methylation occurs almost exclusively at cytosine chains that are followed by guanine. CytosineMethylation.png
Methylation of cytosine to 5- methylcytosine: DNA methylation is the addition of a methyl group to the DNA that happens at cytosine. The image shows a cytosine single ring base and a methyl group added on to the 5 carbon. In mammals, DNA methylation occurs almost exclusively at cytosine chains that are followed by guanine.

The reason for methylation to be almost exclusive to CpG dinucleotides is the symmetry of the dinucleotide. This allows for preservation during cell division and is a hallmark for epigenetic modifications.

In a normal cell, the CpG island is hypomethylated, as can be seen from the unfilled stubs, but the genome, in general, is methylated, as can be seen from the filled in stubs. In contrast, in the cancer cell, the CpG island is more likely to be methylated, and the rest of the genome is hypomethylated. There is a swap of where DNA methylation is found between a normal cell and a cancer cell. DNA methylation in a normal cell vs. in a cancer cell.png
In a normal cell, the CpG island is hypomethylated, as can be seen from the unfilled stubs, but the genome, in general, is methylated, as can be seen from the filled in stubs. In contrast, in the cancer cell, the CpG island is more likely to be methylated, and the rest of the genome is hypomethylated. There is a swap of where DNA methylation is found between a normal cell and a cancer cell.

Role in cancer

CpG islands that are hypermethylated can play three roles in cancer: in diagnosis, prognosis and in monitoring. It is useful to consider a particular tumor type, called CpG island methylator phenotype, or CIMP: higher levels of CpG island hypermethylation are found in CIMP. The frequent occurrence of hypermethylation was first described in colorectal cancer and later for glioma. More recently, it has been studied for neuroblastomas. Colorectal cancer will not necessarily have the same set of hypermethylated CpG islands as in a glioma, and this clinical distinctness of tumors can be interpreted by doctors. Hypermethylated CpG islands also act as biomarkers, as they can help distinguish cancer from normal cells in the same sample.

Colorectal CIMP was one of the first to be described. Patients in this category of cancer tend to be older, female and have a defective MLH1 function. The tumors are usually in the ascending colon. They also have a good prognostic outcome. Clinically distinct phenotypes of CIMP also suggest that there is potential for epigenetic therapy.

In diagnosis, one can identify the tumor type and tumor subtype, as well as its primary tumor when that is unknown. Hypermethylation increases with tumorigenicity, which is an indication of the prognosis of cancer. For example, high methylation is a marker for poor prognosis in lung cancer. CpG island hypermethylation shows promise for molecular monitoring of patients with cancer, and is also a potential target for therapeutic use.

Epigenetic alterations in tumor progression: Epigenetic mistakes are clinically relevant is because they progress over time. The image starts with normal tissue and progresses all the way to metastasis. The global level of methylation decreases as one progresses from normal tissue to metastatic tissue. However, methylation at some CpG islands increases in density. One might be able to use these methylation markers to detect whether a tissue is cancerous or metastatic. Epigenetic alterations in tumour progression.svg
Epigenetic alterations in tumor progression: Epigenetic mistakes are clinically relevant is because they progress over time. The image starts with normal tissue and progresses all the way to metastasis. The global level of methylation decreases as one progresses from normal tissue to metastatic tissue. However, methylation at some CpG islands increases in density. One might be able to use these methylation markers to detect whether a tissue is cancerous or metastatic.

Aberrations in epigenetic control that are seen in cancer pertain to DNA methylation, which can be either locus-specific DNA hypermethylation or genome-wide DNA hypomethylation. Under locus-specific DNA hypermethylation comes CpG island hypermethylation. DNA methylation acts as an alternative to genetic mutation. According to the Knudson hypothesis, cancer is a result of multiple hits to DNA, and DNA methylation can be one such hit. Epigenetic mutations such as DNA methylation are mitotically heritable, but also reversible, unlike gene mutations. The identity of hypermethylated CpG islands varies by the type of tumor. Some single gene examples include MLH1 in colorectal cancer and BRCA1 in breast cancer.

Related Research Articles

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<span class="mw-page-title-main">Neoplasm</span> Abnormal mass of tissue as a result of abnormal growth or division of cells

A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger is removed. This abnormal growth usually forms a mass, when it may be called a tumour or tumor.

Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

<span class="mw-page-title-main">DNA mismatch repair</span> System for fixing base errors of DNA replication

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

<span class="mw-page-title-main">Oncogenomics</span> Sub-field of genomics

Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.

<span class="mw-page-title-main">MLH1</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.

<span class="mw-page-title-main">RASSF1</span> Protein-coding gene in the species Homo sapiens

Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.

<span class="mw-page-title-main">O-6-methylguanine-DNA methyltransferase</span> Mammalian protein found in Homo sapiens

O6-alkylguanine DNA alkyltransferase (also known as AGT, MGMT or AGAT) is a protein that in humans is encoded by the O6-methylguanine DNA methyltransferase (MGMT) gene. O6-methylguanine DNA methyltransferase is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.

<span class="mw-page-title-main">Secreted frizzled-related protein 1</span> Protein-coding gene in the species Homo sapiens

Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.

<span class="mw-page-title-main">RASSF2</span> Protein-coding gene in the species Homo sapiens

Ras association domain-containing protein 2 is a protein that in humans is encoded by the RASSF2 gene.

Methylated DNA immunoprecipitation is a large-scale purification technique in molecular biology that is used to enrich for methylated DNA sequences. It consists of isolating methylated DNA fragments via an antibody raised against 5-methylcytosine (5mC). This technique was first described by Weber M. et al. in 2005 and has helped pave the way for viable methylome-level assessment efforts, as the purified fraction of methylated DNA can be input to high-throughput DNA detection methods such as high-resolution DNA microarrays (MeDIP-chip) or next-generation sequencing (MeDIP-seq). Nonetheless, understanding of the methylome remains rudimentary; its study is complicated by the fact that, like other epigenetic properties, patterns vary from cell-type to cell-type.

<span class="mw-page-title-main">YPEL3</span> Protein-coding gene in humans

Yippee-like 3 (Drosophila) is a protein that in humans is encoded by the YPEL3 gene. YPEL3 has growth inhibitory effects in normal and tumor cell lines. One of five family members (YPEL1-5), YPEL3 was named in reference to its Drosophila melanogaster orthologue. Initially discovered in a gene expression profiling assay of p53 activated MCF7 cells, induction of YPEL3 has been shown to trigger permanent growth arrest or cellular senescence in certain human normal and tumor cell types. DNA methylation of a CpG island near the YPEL3 promoter as well as histone acetylation may represent possible epigenetic mechanisms leading to decreased gene expression in human tumors.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

Melanoma is a rare but aggressive malignant cancer that originates from melanocytes. These melanocytes are cells found in the basal layer of the epidermis that produce melanin under the control of melanocyte-stimulating hormone. Despite the fact that melanoma represents only a small number of all skin cancers, it is the cause of more than 50% of cancer-related deaths. The high metastatic qualities and death rate, and also its prevalence among people of younger ages have caused melanoma to become a highly researched malignant cancer. Epigenetic modifications are suspected to influence the emergence of many types of cancer-related diseases, and are also suspected to have a role in the development of melanoma.

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation. DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes.

DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the promoter hypermethylation where the CPGs islands in the promoter regions are methylated contributing or causing genes to be silenced.

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

References

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  2. ↑ Greger V, Passarge E, Höpping W, Messmer E, Horsthemke B (1 September 1989). "Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma". Human Genetics. 83 (2): 155–8. doi:10.1007/BF00286709. PMID   2550354. S2CID   2058532.
  3. 1 2 3 Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM (11 October 1994). "Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma". Proceedings of the National Academy of Sciences. 91 (21): 9700–4. Bibcode:1994PNAS...91.9700H. doi: 10.1073/pnas.91.21.9700 . PMC   44884 . PMID   7937876.
  4. ↑ Clark J, Rocques PJ, Crew AJ, Gill S, Shipley J, Chan AM, Gusterson BA, Cooper CS (1 August 1994). "Identification of novel genes, SYT and SSX, involved in the t (X; 18)(p11. 2; q11. 2) translocation found in human synovial sarcoma". Nature Genetics. 7 (4): 502–8. doi:10.1038/ng0894-502. PMID   7951320. S2CID   20503729.
  5. 1 2 Esteller M, Corn PG, Baylin SB, Herman JG (15 April 2001). "A gene hypermethylation profile of human cancer". Cancer Research. 61 (8): 3225–9. PMID   11309270.
  6. ↑ Feinberg AP, Vogelstein B (1 July 1983). "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Analytical Biochemistry. 132 (1): 6–13. doi:10.1016/0003-2697(83)90418-9. PMID   6312838.
  7. ↑ University of Melbourne, Coursera
  8. ↑ Illingworth RS, Bird AP (5 June 2009). "CpG islands–'a rough guide'". FEBS Letters. 583 (11): 1713–20. doi: 10.1016/j.febslet.2009.04.012 . PMID   19376112.
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