Cancer occurs when a single progenitor cell accumulates
mutations and other changes in the
DNA,
histones, and other biochemical compounds that make up the cell's
genome. The cell genome controls the structure of the cell's biochemical components, the biochemical reactions that occur within the cell, and the biological interactions of that cell with other cells. Certain combinations of mutations in the given progenitor cell ultimately result in that cell (also called a cancer stem cell) displaying a number of abnormal,
malignant cellular properties that, when taken together, are considered characteristic of cancer, including: • the ability to continue to divide perpetually, producing an exponentially (or near-exponentially) increasing number of new malignant cancerous "daughter cells" (uncontrolled
mitosis); • the ability to penetrate normal body surfaces and barriers, and to bore into or through nearby body structures and tissues (local invasiveness); • the ability to spread to other sites within the body (
metastasize) by penetrating or entering into the
lymphatic vessels (regional metastasis) and/or the
blood vessels (distant metastasis). If this process of continuous growth, local invasion, and regional and distant metastasis is not halted via a combination of stimulation of immunological defenses and medical treatment interventions, the result is that the host has a continuously increasing burden of tumor cells throughout the body. Eventually, the tumor burden increasingly interferes with normal biochemical functions carried out by the host's
organs, and
death ultimately ensues. Carcinoma is but one form of cancer—one composed of cells that have developed the cytological appearance, histological architecture, or molecular characteristics of epithelial cells. a
multipotent cell,
Metastatic carcinoma Metastatic carcinoma is
cancer that is able to grow at sites distant from the primary site of origin; thus, dissemination to the skin may occur with any malignant
neoplasm, and these infiltrates may result from direct invasion of the skin from underlying tumors, may extend by
lymphatic or
hematogenous spread, or may be introduced by therapeutic procedures.
Mutation Whole genome sequencing has established the mutation frequency for whole human genomes. The mutation frequency in the whole genome between generations for humans (parent to child) is about 70 new mutations per generation. Carcinomas, however, have much higher mutation frequencies. The particular frequency depends on tissue type, whether a mis-match DNA repair deficiency is present, and exposure to DNA damaging agents such as components of tobacco smoke. Tuna and Amos have summarized the mutation frequencies per megabase (Mb) in some carcinomas, as shown in the table (along with the indicated frequencies of mutations per genome).
Cause of mutations The likely major underlying cause of mutations in carcinomas is DNA damage. For example, in the case of lung cancer, DNA damage is caused by agents in
exogenous genotoxic tobacco smoke (e.g.
acrolein,
formaldehyde,
acrylonitrile,
1,3-butadiene,
acetaldehyde,
ethylene oxide and
isoprene).
Endogenous (metabolically caused) DNA damage is also very frequent, occurring on average more than 60,000 times a day in the genomes of human cells. Externally and endogenously caused damages may be converted into mutations by inaccurate
translesion synthesis or inaccurate DNA repair (e.g. by
non-homologous end joining).
High frequency The high frequency of mutations in the total genome within carcinomas suggests that, often, an early carcinogenic alteration may be a deficiency in DNA repair. For instance, mutation rates substantially increase (sometimes by 100-fold) in cells defective in
DNA mismatch repair. A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone translesion synthesis past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to
epigenetic alterations or epimutations. While a mutation or epimutation in a DNA repair gene, itself, would not confer a selective advantage, such a repair defect may be carried along as a passenger in a cell when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage. Such cells, with both proliferative advantages and one or more DNA repair defects (causing a very high mutation rate), likely give rise to the high frequency of total genome mutations seen in carcinomas.
DNA repair In somatic cells, deficiencies in DNA repair sometimes arise by mutations in DNA repair genes, but much more often are due to
epigenetic reductions in expression of DNA repair genes. Thus, in a sequence of 113 colorectal carcinomas, only four had somatic missense mutations in the DNA repair gene
MGMT, while the majority of these cancers had reduced MGMT protein expression due to methylation of the
MGMT promoter region. ==Diagnosis==