not keep dna from the beginning of life until a possible cancer occurs. this implies that most cancers arise from normal stem cells. contribution of field defects longitudinally opened freshly resected colon segment showing a cancer and four polyps. plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. the diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors. the term "field cancerization" was first used in 1953 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. since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise. field defects have been identified in association with cancers and are important in progression to cancer. however, it was pointed out by rubin that "the vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion…" more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. 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 its neighbors, 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). in the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3 cm across in its longest dimension). 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 its inner surface 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. frequency of epigenetic changes in dna repair genes in sporadic cancers and in adjacent field defects cancer gene frequency in cancer frequency in field defect reference colorectal mgmt46%34% colorectal mgmt47%11% colorectal mgmt70%60% colorectal msh213%5% colorectal ercc1100%40% colorectal pms288%50% colorectal xpf55%40% head and neck mgmt54%38% head and neck mlh133%25% head and neck mlh131%20% stomach mgmt88%78% stomach mlh173%20% esophagus mlh177%–100%23%–79% some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. in a 1996 study of polyps less than 10mm in size found during colonoscopy and followed with repeat colonoscopies for 3 years, 25% remained unchanged in size, 35% regressed or shrank in size and 40% grew in size. genome instability cancers are known to exhibit genome instability or a "mutator phenotype". the protein-coding dna within the nucleus is about 1.5% of the total genomic dna. within this protein-coding dna (called the exome), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations. however, the average number of dna sequence mutations in the entire genome (including non-protein-coding regions) within a breast cancer tissue sample is about 20,000. in an average melanoma tissue sample (melanomas have a higher exome mutation frequency),) the total number of dna sequence mutations is about 80,000. these high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defect giving rise to a cancer (e.g. yellow area in the diagram in the preceding section) is a deficiency in dna repair. large field defects surrounding colon cancers (extending to about 10 cm on each side of a cancer) are found to frequently have epigenetic defects in two or three dna repair proteins (ercc1, ercc4 (xpf) and/or pms2) in the entire area of the field defect. when expression of dna repair genes is reduced, dna damage accumulates in cells at a higher than normal rate, and this excess damage causes an increased frequency of mutation and/or epimutation. mutation rates strongly increase in cells defective in dna mismatch repair or in homologous recombinational repair (hrr). a deficiency in dna repair, itself, can allow dna damage to accumulate, and error-prone translesion synthesis of some of the damaged areas may give rise to mutations. in addition, faulty repair of this accumulated dna damage may give rise to epimutations. these new mutations and/or epimutations may provide a proliferative advantage, generating a field defect. although the mutations/epimutations in dna repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage. non-mainstream theories 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. this causes an energy switch from oxidative phosphorylation to aerobic glycolysis (warburg's hypothesis), and the accumulation of reactive oxygen species leading to oxidative stress ("oxidative stress theory of cancer"). another concept of cancer development is based on exposure to weak magnetic and electromagnetic fields and their effects on oxidative stress, known as magnetocarcinogenesis. 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. a related theory suggests that cancer is an atavism, an evolutionary throwback to an earlier form of multicellular life. the genes responsible for uncontrolled cell growth and cooperation between cancer cells are very similar to those that enabled the first multicellular life forms to group together and flourish. these genes still exist within the genomes 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. instead, they possess a fixed number of primitive genes that are progressively activated, giving them finite variability. another evolutionary theory puts the roots of cancer back to the origin of the eukaryote (nucleated) cell by massive horizontal gene transfer, when the genomes of infecting viruses were cleaved (and thereby attenuated) by the host, but their fragments integrated into the host genome as immune protection. cancer thus originates when a rare somatic mutation recombines such fragments into a functional driver of cell proliferation. cancer cell biology tissue can be organized in a continuous spectrum from normal to cancer. often, the multiple genetic changes that result in cancer may take many years to accumulate. during this time, the biological behavior of the pre-malignant cells slowly changes from the properties of normal cells to cancer-like properties. pre-malignant tissue can have a distinctive appearance under the microscope. among the distinguishing traits of a pre-malignant lesion are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. these early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation. the most severe cases of dysplasia are referred to as carcinoma in situ. in latin, the term in situ means "in place"; carcinoma in situ refers to an uncontrolled growth of dysplastic cells that remains in its original location and has not shown invasion into other tissues. carcinoma in situ may develop into an invasive malignancy and is usually removed surgically when detected. clonal evolution main article: somatic evolution in cancer just as a population of animals undergoes evolution, an unchecked population of cells also can undergo "evolution". this undesirable process is called somatic evolution, and is how cancer arises and becomes more malignant over time. most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. however, once cancer begins, cancer cells undergo a process of natural selection: the few cells with new genetic changes that enhance their survival or reproduction multiply faster, and soon come to dominate the growing tumor as cells with less favorable genetic change are out-competed. this is the same mechanism by which pathogenic species such as mrsa can become antibiotic-resistant and by which hiv can become drug-resistant), and by which plant diseases and insects can become pesticide-resistant. this evolution explains why a cancer relapse often involves cells that have acquired cancer-drug resistance or resistance to radiotherapy). biological properties