As one example of an exogenous carcinogeneic agent, tobacco smoke causes increased DNA damage, and these DNA damages likely cause the increase of lung cancer due to smoking. DNA damages can also be caused by endogenous naturally occurring agents. Macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis,  and bile acids, at high levels in the colons of humans eating a high fat diet, also cause DNA damage and contribute to colon cancer.
Such exogenous and endogenous sources of DNA damage are indicated in the boxes at the top of the figure in this section. The central role of DNA damage in progression to cancer is indicated at the second level of the figure. The central elements of DNA damage, epigenetic alterations and deficient DNA repair in progression to cancer are shown in red. However, such germline mutations which cause highly penetrant cancer syndromes are the cause of only about 1 percent of cancers.
The majority of cancers are called non-hereditary or "sporadic cancers". In sporadic cancers, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. This is indicated in the figure at the 3rd level from the top.
This is shown in the figure at the 4th level from the top. Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair   or in Homologous recombinational repair HRR. The somatic mutations and epigenetic alterations caused by DNA damages and deficiencies in DNA repair accumulate in field defects. Field defects are normal appearing tissues with multiple alterations discussed in the section below , and are common precursors to development of the disordered and improperly proliferating clone of tissue in a cancer.
Such field defects second level from bottom of figure may have multiple mutations and epigenetic alterations.
RSC Publishing. Rethinking metastasis". Similarly, because PARP1 participates not only in DNA repair but also in the pdependent cell-cycle check-point after DNA damage, we believe that cell death control via the regulation of PARP1 activity might be useful for future applications in cancer therapy. University of California San Diego Professor Susan Ackerman and her colleagues first highlighted this cause of brain disease more than 10 years ago. Seminars in Cutaneous Medicine and Surgery.
It is impossible to determine the initial cause for most specific cancers. In a few cases, only one cause exists; for example, the virus HHV-8 causes all Kaposi's sarcomas.
However, with the help of cancer epidemiology techniques and information, it is possible to produce an estimate of a likely cause in many more situations. For example, lung cancer has several causes, including tobacco use and radon gas.
Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking. Among the more than 5, compounds in tobacco smoke, the genotoxic DNA damaging agents that occur both at the highest concentrations and which have the strongest mutagenic effects are acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene. Using molecular biological techniques, it is possible to characterize the mutations, epimutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases.
For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize , spreading to other parts of the body.
However, once a cancer is formed it continues to evolve and to produce sub clones.
For example, a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, 59 mutations shared by some, but not all regions, and 29 "private" mutations only present in one region. The cells in which all these DNA alterations accumulate are difficult to trace, but two recent lines of evidence suggest that normal stem cells may be the cells of origin in cancers.
The correlation applied to 31 cancer types and extended across five orders of magnitude. If they divide 1, times, the cancer risk is 1,X. And if the normal stem cells from a tissue divide , times, the cancer risk in that tissue is approximately ,X. This strongly suggests that the main reason we have cancer is that our normal stem cells divide, which implies that cancer originates in normal stem cells.
A possible explanation is that cancers occur because cells accumulate damage through time. DNA is the only cellular component that can accumulate damage over the entire course of a life, and stem cells are the only cells that can transmit DNA from the zygote to cells late in life. Other cells cannot keep DNA from the beginning of life until a possible cancer occurs. This implies that most cancers arise from normal stem cells.
The term "field cancerization" was first used in to describe an area or "field" of epithelium that has been preconditioned by at that time largely unknown processes so as to predispose it towards development of cancer. Field defects have been identified in association with cancers and are important in progression to cancer.
It would also be expected that many of the epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects. In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the intestinal crypts on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. This may cause a patch of abnormal tissue to arise. The figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps.
Below the photo there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram a large clone of cells , a second such mutation or epigenetic alteration may occur so that a given stem cell acquires an advantage compared to other stem cells within the patch, and this altered stem cell may expand clonally forming a secondary patch, or sub-clone, within the original patch.
This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches sub-clones , the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches with still different colors in the diagram which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm cancer. These neoplasms are also indicated in the diagram below the photo by 4 small tan circles polyps and a larger red area cancer.
The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine labeled and where the appendix occurs labeled. The fat in the photo is external to the outer wall of the colon.
In the segment of colon shown here, the colon was cut open lengthwise to expose the inner surface of the colon and to display the cancer and polyps occurring within the inner epithelial lining of the colon. If the general process by which sporadic colon cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed by formation of internal sub-clones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality reflecting the succession of premalignant events.
The most extensive region of abnormality the outermost yellow irregular area in the diagram would reflect the earliest event in formation of a malignant neoplasm. In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The Table, below, gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically caused DNA repair deficiency was found in the surrounding field defect.
Some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. Cancers are known to exhibit genome instability or a mutator phenotype. Mutation rates strongly increase in cells defective in DNA mismatch repair   or in homologous recombinational repair HRR. In addition, faulty repair of these accumulated DNA damages may give rise to epimutations. There are a number of theories of carcinogenesis and cancer treatment that fall outside the mainstream of scientific opinion, due to lack of scientific rationale, logic, or evidence base.
These theories may be used to justify various alternative cancer treatments.
They should be distinguished from those theories of carcinogenesis that have a logical basis within mainstream cancer biology, and from which conventionally testable hypotheses can be made. Several alternative theories of carcinogenesis, however, are based on scientific evidence and are increasingly being acknowledged. Some researchers believe that cancer may be caused by aneuploidy numerical and structural abnormalities in chromosomes  rather than by mutations or epimutations. Cancer has also been considered as a metabolic disease in which the cellular metabolism of oxygen is diverted from the pathway that generates energy oxidative phosphorylation to the pathway that generates reactive oxygen species.
Aberrant DNA methylation patterns — hypermethylation and hypomethylation compared to normal tissue — have been associated with a large number of human malignancies. See DNA methylation in cancer. A number of authors have questioned the assumption that cancers result from sequential random mutations as oversimplistic, suggesting instead that cancer results from a failure of the body to inhibit an innate, programmed proliferative tendency.
These genes still exist within the genome of more complex metazoans , such as humans, although more recently evolved genes keep them in check. When the newer controlling genes fail for whatever reason, the cell can revert to its more primitive programming and reproduce out of control. The theory is an alternative to the notion that cancers begin with rogue cells that undergo evolution within the body.