genome. The average number of DNA sequence mutations in the entire genome of breast cancer tissue is about 20,000. In an average melanoma (where melanomas have a higher exome mutation frequency) the total number of DNA sequence mutations is about 80,000. Epigenetic alterations Transcription silencing A second underlying commonality in cancers is altered epigenetic regulation of transcription. In cancers, loss of gene expression occurs about 10 times more frequently by epigenetic transcription silencing (caused, for example, by promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker, or passenger, mutations. In contrast, the frequency of epigenetic alterations is much higher. In colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while the corresponding CpG islands are not methylated in the adjacent mucosa. Such methylation turns off expression of a gene as completely as a mutation would. Around 60–70% of human genes have a CpG island in their promoter region. In colon cancers, in addition to hypermethylated genes, several hundred other genes have hypomethylated (under-methylated) promoters, thereby causing these genes to be turned on when they ordinarily would be turned off. Post-transcriptional silencing Epigenetic alterations are also carried out by another major regulatory element, that of microRNAs (miRNAs). In mammals, these small non-coding RNA molecules regulate about 60% of the transcriptional activity of protein-encoding genes. Epigenetic silencing or epigenetic over-expression of miRNA genes, caused by aberrant DNA methylation of the promoter regions controlling their expression, is a frequent event in cancer cells. Almost one third of miRNA promoters active in normal mammary cells were found to be hypermethylated in breast cancer cells, and that is a several fold greater proportion of promoters with altered methylation than is usually observed for protein coding genes. Other microRNA promoters are hypomethylated in breast cancers, and, as a result, these microRNAs are over-expressed. Several of these over-expressed microRNAs have a major influence in progression to breast cancer. BRCA1 is normally expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. BRCA1 is involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double-strand breaks. BRCA1 expression is