Epigenetic Hallmarks of Cancer

Salser's observation in 1977 that 5mC was responsible for the mutation of CpG dinucleotides prompted investigators to determine whether the natural patterns of methylation were disturbed in human neoplasia.14 The first change to be reported for a number of cancers by Andrew Feinberg and colleagues was loss of methylation at the level of individual genes and globally.108,109 In four of five patients, representing two different types of cancer, Southern blots revealed substantial hypomethylation in genes of cancer cells compared to their normal counterparts; in one of these patients hypomethylation was progressive in a metastasis.108 Such a loss appeared to be ubiquitous for human neoplasms, whereas hypomethylation was the only type of change observed in benign neoplasms. A generalized decrease in genomic methylation was also noted as cells age, and this gradual loss could result in aberrant gene activation.

The second notable change observed in many human cancers was hyperme-thylation, particularly of CpG islands at gene promoters.110 A very recent study has shown that promoter hypermethylation of genes involving important cellular pathways in tumorigenesis is a prominent feature of many major human tumor types.71 Hypermethylation, which is often accompanied by global hypomethylation, could act as an alternative to mutations that inactivate tumor-suppressor genes and it also could predispose to genetic alterations through inactivation of DNA repair genes.

The third important change is LOI. In cancer, LOI can lead to activation of growth-promoting genes such as IGF2, and to silencing of tumor suppressor genes,111-113 as already noted.

The full range of epigenetic change that occurs in human cancers is not known, but hypomethylation, hypermethylation at CpG islands, and LOI occur most frequently.114 An early study of p53 illustrates what might be learned from a study of 5mC mutations in human tissues.115 p53 is a well-known tumor suppressor gene that has been studied intensively. Normally in a cell, p53 is kept at very low levels, but DNA damage results in a rapid increase and its activation as a transcription factor. As a transcription factor, p53 either arrests the cells in the G1 phase of the cell cycle or triggers apoptosis.116 More than 4500 mutations have been identified in the p53 gene, and p53 mutations are found in 50-55% of all human cancers. Three codons in p53 (175, 273, and 248) are of particular interest because they are hotspots for point mutations that impair p53 function in cancer. Sequencing indicates that all three of these codons contain 5mC which is mutated in various tumors. Rideout et al. found that as many as 43% (9 of 21) of the p53 somatic mutations at these sites are due to 5mC. There are 82 CpGs in the 2362 nucleotides of the double-stranded coding sequence of p53. The relevance of methylation to mutations in p53 is brought out more clearly by the fact that no more than ~3.5% (82/2362) of the sequence contributed 33-43% of the point mutations, each of which was a transition from 5mC to thymine (or a corresponding G to A )115 (Figure 6.1).

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

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