Mutations One underlying commonality in cancers is genetic mutation, acquired either by inheritance, or, more commonly, by mutations in one's
somatic DNA over time. The mutations considered important in cancers are those that alter protein coding genes (the
exome). As Vogelstein et al. point out, a typical tumor contains two to eight exome "driver gene" mutations, and a larger number of exome mutations that are "passengers" that confer no selective growth advantage. Cancers also generally have
genome instability, that includes a high frequency of mutations in the
noncoding DNA that makes up about 98% of the human 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
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. 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. 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 reduced or undetectable in the majority of high grade, ductal breast cancers. Only about 3–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.
BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas. However, breast cancers were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue. In breast cancer cell lines, there is an inverse correlation of
BRCA1 protein levels with miR-182 expression. Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182. In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation. Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.
Post-transcriptional regulation by microRNA occurs either through translational silencing of the target mRNA or through degradation of the target mRNA, via complementary binding, mostly to specific sequences in the
three prime untranslated region of the target gene's mRNA. The mechanism of translational silencing or degradation of target mRNA is implemented through the
RNA-induced silencing complex (RISC).
DNA repair gene silencing Silencing of a DNA repair gene by
hypermethylation or other
epigenetic alteration appears to be a frequent step in progression to cancer. As summarized in a review, promoter hypermethylation of DNA repair gene
MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers. In addition, promoter hypermethylation of DNA repair genes
LIG4,
NEIL1,
ATM,
MLH1 or
FANCB occurs at frequencies of between 33% and 82% in one or more of
head and neck cancers,
non-small-cell lung cancers or
non-small-cell lung cancer squamous cell carcinomas. Further, the article
Werner syndrome ATP-dependent helicase indicates the DNA repair gene
WRN has a promoter that is often hypermethylated in a variety of cancers, with
WRN hypermethylation occurring in 11% to 38% of
colorectal,
head and neck,
stomach,
prostate,
breast,
thyroid,
non-Hodgkin lymphoma,
chondrosarcoma and
osteosarcoma cancers. Such silencing likely acts similarly to a germ-line mutation in a DNA repair gene, and predisposes the cell and its descendants to progression to cancer. Another review points out that when a gene necessary for DNA repair is epigenetically silenced, DNA repair would tend to be deficient and DNA damages can accumulate. Increased DNA damage can cause increased errors during DNA synthesis, leading to mutations that give rise to cancer. ==Clinical signs==