Description

Patterns of DNA methylation are typically transmitted to daughter cells with high fidelity in somatic cells. This methylation typically only takes place at cytosines that are located to guanosine in the CpG dinucleotides of higher order eukaryotes. However, epigenetic DNA methylation is distinct between normal cells and human tumor cells. In tumorigenic cells, the "normal" CpG methylation profile is frequently reversed. In normal cells, CpG islands preceding gene promoters are typically unmethylated and transcriptionally active, whereas other CPG dinucleotides in the genome are typically methylated. However, CpG methylation of oncogene promoter regions and parasitic repeat sequences is frequently decreased in cancer cells, while CpG methylation of tumor suppressor gene promoter regions is frequently hypermethylated. Hypermethylation of tumor suppressor gene promoter regions can result in the silencing of those genes. The addition of methyl groups to cytosines causes the DNA to tightly coil around the histone proteins, resulting in DNA that cannot undergo transcription (transcriptionally silenced DNA), which in turn leads to tumorigenesis. Due to promoter hypermethylation, transcriptionally silenced genes frequently include: p16, a cell cycle inhibitor, is a cyclin-dependent kinase inhibitor. DNA repair gene MGMT; a cell cycle regulator called APC; DNA repair gene MLH1; CpG dinucleotide hypomethylation in other parts of the genome leads to chromosome instability due to mechanisms such as loss of imprinting and reactivation of transposable elements. Loss of imprinting of Insulin-Like Growth Factor (IGF) increases risk of colorectal cancer and is associated with Beckwith-Wiedemann syndrome, which significantly increases risk of cancer for newborns.

The whole genome of a carcinogenic cell contains fundamentally less methylcytosine than the genome of a solid cell. CpG islands in promoter regions are typically shielded from DNA methylation, so cancer cell genomes have 20-50% less methylation at individual CpG dinucleotides across the genome. CpG islands are hypomethylated in cancer cells. In the context of a CpG dinucleotide, the majority of DNA methylation takes place in the CpG island shores region. At the CpG island shores, cancer cells are deferentially methylated. CpG island methylation is important for regulating gene expression, but cytosine methylation can directly lead to destabilizing genetic mutations and a precancerous cellular state. In cancer cells, "global hypomethylation" caused by disruption in DNA methyltransferases may promote mitotic recombination and chromosome rearrangement, ultimately resulting in aneuploidy when the chromosomes fail to separate properly during mitosis.  Hydrolysis of the amine group and spontaneous conversion to thymine are facilitated by methylated cytosines. Chromatin proteins' abnormal recruitment may be triggered by them. Pyrimidine dimers are produced when cytosine methylations alter the amount of UV light absorption by the nucleotide base. These genes may become inactive when mutation causes heterozygosity loss at tumor suppressor gene locations. During replication, single base pair mutations can also have negative effects.

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 CpG islands in the promoter regions are methylated contributing or causing genes to be silenced. All mammalian cells descended from a fertilized egg share a common DNA sequence. However, during development and formation of different tissues epigenetic factors change. The changes include histone modifications, CpG island methylations and chromatin reorganizations which can cause the stable silencing or activation of particular genes. Once differentiated tissues are formed, CpG island methylation is generally stably inherited from one cell division to the next through the DNA methylation maintenance machinery. In cancer, a number of mutational changes are found in protein coding genes. However, transcriptional silencing may be more important than mutation in causing gene silencing in progression to cancer. Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs.

Thanks & Regards
Jackson
Journal coordinator
Journal of Neoplasm