Exposure to particular substances have been linked to specific types of cancer. These substances are called "carcinogens".

Tobacco smoke, for example, causes 90% of lung cancer. It also causes cancer in the larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas. Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.

Tobacco is responsible for about one in five cancer deaths worldwide and about one in three in the developed world. Lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking rates since the 1950s followed by decreases in lung cancer death rates in men since 1990.

In Western Europe, 10% of cancers in males and 3% of cancers in females are attributed to alcohol exposure, especially liver and digestive tract cancers. Cancer from work-related substance exposures may cause between 2 and 20% of cases, causing at least 200,000 deaths. Cancers such as lung cancer and mesothelioma can come from inhaling tobacco smoke or asbestos fibers, or leukemia from exposure to benzene.

Up to 10% of invasive cancers are related to radiation exposure, including both ionizing radiation and non-ionizing ultraviolet radiation. Additionally, the majority of non-invasive cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation, mostly from sunlight. Sources of ionizing radiation include medical imaging and radon gas.

Ionizing radiation is not a particularly strong mutagen. Residential exposure to radon gas, for example, has similar cancer risks as passive smoking. Radiation is a more potent source of cancer when combined with other cancer-causing agents, such as radon plus tobacco smoke. Radiation can cause cancer in most parts of the body, in all animals and at any age. Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.

Medical use of ionizing radiation is a small but growing source of radiation-induced cancers. Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a second form of cancer. It is also used in some kinds of medical imaging.

Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies. Clear evidence establishes ultraviolet radiation, especially the non-ionizing medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.

Non-ionizing radio frequency radiation from mobile phones, electric power transmission and other similar sources have been described as a possible carcinogen by the World Health Organization's International Agency for Research on Cancer. However, studies have not found a consistent link between mobile phone radiation and cancer risk.

Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies. Clear evidence establishes ultraviolet radiation, especially the non-ionizing medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.

Skin cancer may occur following ionizing radiation exposure following a latent period averaging 20 to 40 years. A Chronic radiation keratosis is a precancerous keratotic skin lesion that may arise on the skin many years after exposure to ionizing radiation. Various malignancies may develop, most frequency basal-cell carcinoma followed by squamous-cell carcinoma. Elevated risk is confined to the site of radiation exposure. Several studies have also suggested the possibility of a causal relationship between melanoma and ionizing radiation exposure. The degree of carcinogenic risk arising from low levels of exposure is more contentious, but the available evidence points to an increased risk that is approximately proportional to the dose received. Radiologists and radiographers are among the earliest occupational groups exposed to radiation. It was the observation of the earliest radiologists that led to the recognition of radiation-induced skin cancer—the first solid cancer linked to radiation—in 1902. While the incidence of skin cancer secondary to medical ionizing radiation was higher in the past, there is also some evidence that risks of certain cancers, notably skin cancer, may be increased among more recent medical radiation workers, and this may be related to specific or changing radiologic practices. Available evidence indicates that the excess risk of skin cancer lasts for 45 years or more following irradiation.

Cancer is a stochastic effect of radiation, meaning that it only has a probability of occurrence, as opposed to deterministic effects which always happen over a certain dose threshold. The consensus of the nuclear industry, nuclear regulators, and governments, is that the incidence of cancers due to ionizing radiation can be modeled as increasing linearly with effective radiation dose at a rate of 5.5% per sievert. Individual studies, alternate models, and earlier versions of the industry consensus have produced other risk estimates scattered around this consensus model. There is general agreement that the risk is much higher for infants and fetuses than adults, higher for the middle-aged than for seniors, and higher for women than for men, though there is no quantitative consensus about this. This model is widely accepted for external radiation, but its application to internal contamination is disputed. For example, the model fails to account for the low rates of cancer in early workers at Los Alamos National Laboratory who were exposed to plutonium dust, and the high rates of thyroid cancer in children following the Chernobyl accident, both of which were internal exposure events. The European Committee on Radiation Risk calls the ICRP model "fatally flawed" when it comes to internal exposure.

Radiation can cause cancer in most parts of the body, in all animals, and at any age, although radiation-induced solid tumors usually take 10–15 years, and can take up to 40 years, to become clinically manifest, and radiation-induced leukemias typically require 2–10 years to appear. Some people, such as those with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developing cancer from radiation exposure. Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.

Radiation exposure can cause cancer in any living tissue, but high-dose whole-body external exposure is most closely associated with leukemia, reflecting the high radiosensitivity of bone marrow. Internal exposures tend to cause cancer in the organs where the radioactive material concentrates, so that radon predominantly causes lung cancer, iodine-131 is most likely to cause thyroid cancer, etc.

Cancer prevalence in dogs increases with age and certain breeds are more susceptible to specific kinds of cancers. Millions of dogs develop spontaneous tumors each year. Boxers, Boston Terriers and Golden Retrievers are among the breeds that most commonly develop mast cell tumors. Large and giant breeds, like Great Danes, Rottweilers, Greyhound and Saint Bernards, are much more likely to develop bone cancer than smaller breeds. Lymphoma occurs at increased rates in Bernese Mountain dogs, bulldogs, and boxers. It is important for the owner to be familiar with the diseases to which their specific breed of dog might have a breed predisposition.

The prevention of feline cancer mainly depends on the cat's diet and lifestyle, as well as an ability to detect early signs and symptoms of cancer prior to advancement to a further stage. If cancer is detected at an earlier stage, it has a higher chance of being treated, therefore lessening the chances of fatality. Taking domesticated cats for regular checkups to the veterinarian can help spot signs and symptoms of cancer early on and help maintain a healthy lifestyle. Further, due to advancements in research, prevention of certain types of feline illnesses remains possible. A widely known preventative of feline leukemia virus is the vaccine which was created in 1969. Subsequently, an immunofloures-cent antibody (IFA) test for the detection of FeLV in the blood of infected cats was formulated. The IFA test was mainly used to experiment the chances of felines being exposed to cancer. The results showed that 33% of cats who were exposed to FeLV related diseases were at a higher risk for acquiring it, while the cats that were left unexposed were left unaffected. FeLV is either spread through contagion or infection and once infected it is possible for cats to stay that way for the rest of their lives.

Interaction with other Cats

Interaction with other cats with strains or diseases related to FeLV can be a great risk factor for cats attaining FeLV themselves. Therefore, a main factor in prevention is keeping the affected cats in quarantine from the unaffected cats. Stray cats, or indoor/outdoor cats have been shown to be at a greater risk for acquiring FeLV, since they have a greater chance of interacting with other cats. Domesticated cats that are kept indoors are the least vulnerable to susceptible diseases.

Vaccines

Vaccines help the immune system fight off disease causing organisms, which is another key to prevention. However, vaccines can also cause tumors if not given properly. Vaccines should be given in the right rear leg to ease tumor removal process. Vaccines given in the neck or in between the shoulder blades are most likely to cause tumors and are difficult to remove, which can be fatal to cats. Reducing the number of vaccinations given to a cat may also decrease the risk for it developing a tumor.

Spaying and Neutering

Spaying and neutering holds many advantages to cats, including lowering the risk for developing cancer. Neutering male cats makes them less subjected to testicular cancer, FeLV, and FIV. Spaying female cats lowers the risk for mammary cancer, ovarian, or uterine cancer, as it prevents them from going into heat. Female cats should be spayed before their first heat, as each cycle of heat creates a greater risk for mammary cancer. Spaying a female cat requires the removal of the ovaries and uterus, which would eliminate their chances of developing cancer in these areas.

Exposure to Sun

The risk of skin cancer increases when a cat is exposed to direct sunlight for prolonged periods. White cats, or cats with white faces and ears, should not be allowed out on sunny days. Between the hours of 10:00 am to 4:00 pm, it is recommended to keep domesticated cats indoors, as the sun is at its highest peak between these times. Sun block is also available for cats, which can help prevent skin irritation, and a veterinarian should be contacted to find out which brands are appropriate and to use on cats.

Exposure to Secondhand Smoke

Cats living in a smoker’s household are three times more likely to develop lymphoma. Compared to living in a smoke-free environment, cats exposed to secondhand smoke also have a greater chance of developing squamous cell carcinoma or mouth cancer. Cancer is also developed mostly due to the cat's grooming habits. As cats lick themselves while they groom, they increase chances of taking in the toxic, cancer-causing carcinogens that gather on their fur, which are then exposed to their mucus membranes.

Lifestyle

Providing a cat with the healthiest lifestyle possible is the key to prevention. Decreasing the amount of toxins, including household cleaning products, providing fresh and whole foods, clean and purified water, and reducing the amount of indoor pollution can help cats live a longer and healthier life. To lessen susceptibility to diseases, domesticated cats should be kept inside the household for most of their lives to reduce the risk of interacting with other stray cats that could be infected with diseases.

Smoking increases the risk of developing gastric cancer significantly, from 40% increased risk for current smokers to 82% increase for heavy smokers. Gastric cancers due to smoking mostly occur in the upper part of the stomach near the esophagus. Some studies show increased risk with alcohol consumption as well.

Laboratory cats have been used in research for a wide range of diseases including stroke and diabetes to AIDS. Less than 1% of research on animal illnesses have been dedicated to cats.

Despite opposition from organizations such as those advocating animal rights, controversial animal testing is still used in cancer research centers. These research practices are continually being conducted on the basis that its benefits to humans outweigh the costs to humans, despite the unfair costs to innocent non-human animals. In some US states, animal testing laboratories get some of their feline test subjects from animal shelters.

According to Kim Sterling, associate teaching professor of oncology at the University of Missouri College of Veterinary Medicine, the use of small animals in predicting human health care procedures is of significant benefit to humans because they are affected in similar, but not exactly the same, ways by the same diseases. This is the same analogy used in reference to cats and their unwilling role in advancing human cancer treatment research.

It is research like this that has led to a potential link between cat parasites and brain cancer in humans. Cats carry the parasite toxoplasma gondii. According to research ecologist Kevin Lafferty, of the University of California, Santa Barbara, this parasite is known to “behave in ways that could stimulate cells towards cancerous states”.

Therefore, research on cats with this parasite can help to better understand the risks of brain cancer for humans in contact with such cats.

Cats have also been used to further studies in the field of Cancer stem cell research. Small animals, like cats, experience faster rates of cancer development. As a result, they are good preclinical models for understanding processes like immortalization and its role in promoting cancerous tumors. The absence of immortalization means a cell can no longer undergo malignant transformation. Since these transformations are the basis for cancerous cell reproduction, this research can prove useful for future cancer treatments and understanding how to stop the spread of cancer in the body.

However, feline cancer research is not limited to what laboratory cats can do for other animals, there is also research being done by humans to see what can be done to improve treatment options for feline cancer. Advances, though slower than that in other animals, are being made in the field of feline cancer. This includes advances in chemotherapy research, immunization protocols and radiation therapy. In addition, there are clinical trials offering trial research treatment options for cats with cancer.

One of such treatments is the cat's claw. Although they share the same name, the cat’s claw (also known as "Uncaria tomentosa" or uña de gato) refers not to the animal cat but to a native plant of the Amazon Rainforest in Peru, South America. Cat's claw is still under research for its immunotherapic, antiproliferative abilities in suppressing cancer proliferation in humans; however, it has been deemed suitable for cat cancer treatment.

Nonetheless, feline cancer research into this, as well as other treatment options, remains an ongoing process.

Dietary factors are not proven causes, but some foods including smoked foods, salt and salt-rich foods, red meat, processed meat, pickled vegetables, and bracken are associated with a higher risk of stomach cancer. Nitrates and nitrites in cured meats can be converted by certain bacteria, including "H. pylori", into compounds that have been found to cause stomach cancer in animals.

Fresh fruit and vegetable intake, citrus fruit intake, and antioxidant intake are associated with a lower risk of stomach cancer. A Mediterranean diet is associated with lower rates of stomach cancer, as is regular aspirin use.

Obesity is a physical risk factor that has been found to increase the risk of gastric adenocarcinoma by contributing to the development of gastroesophageal reflux disease (GERD). The exact mechanism by which obesity causes GERD is not completely known. Studies hypothesize that increased dietary fat leading to increased pressure on the stomach and the lower esophageal sphincter, due to excess adipose tissue, could play a role, yet no statistically significant data has been collected. However, the risk of gastric cardia adenocarcinoma, with GERD present, has been found to increase more than 2 times for an obese person. There is a correlation between iodine deficiency and gastric cancer.

Cancer is a complex, multifactorial disease. Carcinogenesis is linked with DNA mutations, chromosomal translocations, chocolate, dysfunctional proteins, and aberrant cell cycle regulators. Cancer alters the DNA of cells and the mutated genetic material is passed on to daughter cells, resulting in neoplasms. The mutated DNA effects genes involved with the cell cycle, classified as either oncogenes or tumor suppressor genes. Oncogenes are responsible for cell proliferation and differentiation. Oncogenes responsible for cell growth are overexpressed in cancerous cells. Tumor suppressor genes prevent cells with erroneous cell cycles from replicating. Cancer cells ignore cell cycle regulators that control cell growth, division, and death.

The histology of spontaneous tumorigenesis in canines is attributed to the multiplicity and complexity of the disease. The heterogeneity of its development encompasses inherited, epigenetic, and environmental factors.

The selective breeding techniques used with domestic dogs causes certain breeds to be at high risk for specific cancers. Selection for specific phenotypes in dog breeding causes long-range linkage disequilibrium in their DNA. Certain areas of alleles have the tendency to separate less frequently than normal random segregation, which leads to long ranges of repeated DNA sequences. These repeated sequences caused by decreased genetic diversity within breeds, can lead to a high prevalence of certain diseases and especially cancer in breeds.

A transmissible cancer is a cancer cell or cluster of cancer cells that can be transferred between individuals without the involvement of an infectious agent, such as an oncovirus. Transmission of cancer between humans is rare.

Contagious cancers occur in dogs, Tasmanian devils, Syrian hamsters, and some marine bivalves including soft-shell clams. These cancers have a relatively stable genome as they are transmitted.

In humans, a significant fraction of Kaposi's sarcoma occurring after transplantation may be due to tumorous outgrowth of donor cells. Although Kaposi's sarcoma is caused by a virus (Kaposi's sarcoma-associated herpesvirus), in these cases, it appears likely that transmission of virus-infected tumor cells—rather than the free virus—caused tumors in the transplant recipients.

Lymphoma is the most common type of blood-related cancer in horses and while it can affect horses of all ages, it typically occurs in horses aged 4–11 years.

This type of cancer occurs most often in Caucasians between 60 and 80 years of age, and its rate of incidence is about twice as high in males as in females. There are roughly 1,500 new cases of MCC diagnosed each year in the United States, as compared to around 60,000 new cases of melanoma and over 1 million new cases of nonmelanoma skin cancer. MCC is sometimes mistaken for other histological types of cancer, including basal cell carcinoma, squamous cell carcinoma, malignant melanoma, lymphoma, and small cell carcinoma, or as a benign cyst. Researchers believe that exposure to sunlight or ultraviolet light (such as in a tanning bed) may increase the risk of developing this disease. Similar to melanoma, the incidence of MCC in the US is increasing rapidly.

Immunosuppression can profoundly increase the odds of developing Merkel-cell carcinoma. Merkel-cell carcinoma occurs 30 times more often in people with chronic lymphocytic leukemia and 13.4 times more often in people with advanced HIV as compared to the general population; solid organ transplant recipients have a 10-fold increased risk compared to the general population.

Animals that have undergone population bottlenecks may be at greater risks of contracting transmissible cancers. Because of their transmission, it was initially thought that these diseases were caused by the transfer of oncoviruses, in the manner of cervical cancer caused by HPV.

- Canine transmissible venereal tumor (CTVT) is sexually transmitted cancer in dogs. It was experimentally transplanted between dogs in 1876 by M. A. Novinsky (1841–1914). A single malignant clone of CTVT cells has colonized dogs worldwide, representing the oldest known malignant cell line in continuous propagation.

- Contagious reticulum cell sarcoma of the Syrian hamster can be transmitted from one Syrian hamster to another by means of the bite of the mosquito "Aedes aegypti".

- Devil facial tumour disease (DFTD) is a transmissible parasitic cancer in the Tasmanian devil.

- Soft-shell clams, "Mya arenaria", have been found to be vulnerable to a transmissible neoplasm of the hemolymphatic system — effectively, leukemia.

- Horizontally transmitted cancers have also been discovered in three other species of marine bivalves: bay mussels ("Mytilus trossulus"), common cockles ("Cerastoderma edule") and golden carpet shell clams ("Polititapes aureus"). The golden carpet shell clam cancer was found to have been transmitted from another species, the pullet carpet shell ("Venerupis corrugata").

A newly discovered virus called Merkel cell polyomavirus (MCV) likely contributes to the development of the majority of MCC. Approximately 80% of MCC have this virus integrated in a monoclonal pattern, indicating that the infection was present in a precursor cell before it became cancerous. At least 20% of MCC tumors are not infected with MCV, suggesting that MCC may have other causes as well.

Polyomaviruses have been known to be oncogenic (cancer-causing) viruses in animals since the 1950s, but MCV is the first polyomavirus strongly suspected to cause tumors in humans. Like other tumor viruses, most people who are infected with MCV probably do not develop MCC. It is currently unknown what other steps or co-factors are required for MCC-type cancers to develop. MCC can also occur together with other sun exposure-related skin cancers that are not infected with MCV (i.e. basal cell carcinoma, squamous cell carcinoma, melanoma). Intriguingly, most MCV viruses obtained so far from tumors have specific mutations that render the virus uninfectious. It is unknown whether these particular mutations result from sun exposure. MCC also occurs more frequently than would otherwise be expected among immunosuppressed patients, such as transplant patients, AIDS patients, and the elderly persons, suggesting that the initiation and progression of the disease is modulated by the immune system.

While infection with MCV is common in humans, MCC patients whose tumors contain MCV have higher antibody levels against the virus than similarly infected healthy adults. A recent study of a large patient registry from Finland suggests that individuals with MCV-positive MCC's have better prognoses than do MCC patients without MCV infection. While MCV-positive MCC may be a less aggressive form of the disease, the results of the aforementioned study may instead be due to significant differences in other confounding factors, including tumor stage at the time of diagnosis, the age of the patient, or the location of the tumor rather than any intrinsic difference in disease aggressiveness or response to therapy.

In male dogs, the tumor affects the penis and foreskin. In female dogs, it affects the vulva. Rarely, the mouth or nose are affected. The tumor often has a cauliflower-like appearance. Signs of genital TVT include a discharge from the prepuce and in some cases urinary retention, from blockage of the urethra. Signs of a nasal TVT include nasal fistulae, nosebleeds and other nasal discharge, facial swelling, and enlargement of the submandibular lymph nodes.

Globally testicular cancer resulted in 8,300 deaths in 2013 up from 7,000 deaths in 1990. Testicular cancer has the highest prevalence in the U.S. and Europe, and is uncommon in Asia and Africa. Worldwide incidence has doubled since the 1960s, with the highest rates of prevalence in Scandinavia, Germany, and New Zealand.

Although testicular cancer is most common among men aged 15–40 years, it has three peaks: infancy through the age of four as teratomas and yolk sac tumors, ages 25–40 years as post-pubertal seminomas and nonseminomas, and from age 60 as spermatocytic seminomas.

Germ cell tumors of the testis are the most common cancer in young men between the ages of 15 and 35 years.

Surgery may be difficult due to the location of these tumors. Surgery alone often leads to recurrence. Chemotherapy is very effective for TVTs. The prognosis for complete remission with chemotherapy is excellent. The most common chemotherapy agents used are vincristine, vinblastine, and doxorubicin. Radiotherapy may be required if chemotherapy does not work.

While sarcoids may spontaneously regress regardless of treatment in some instances, course and duration of disease is highly unpredictable and should be considered on a case-by-case basis taking into account cost of the treatment and severity of clinical signs. Surgical removal alone is not effective, with recurrence occurring in 50 to 64% of cases, but removal is often done in conjunction with other treatments. Topical treatment with products containing bloodroot extract (from the plant "Sanguinaria canadensis") for 7 to 10 days has been reported to be effective in removing small sarcoids, but the salve's caustic nature may cause pain and the sarcoid must be in an area where a bandage can be applied. Freezing sarcoids with liquid nitrogen (cryotherapy) is another affordable method, but may result in scarring or depigmentation. Topical application of the anti-metabolite 5-fluorouracil has also obtained favorable results, but it usually takes 30 to 90 days of repeated application before any effect can be realized. Injection of small sarcoids (usually around the eyes) with the chemotherapeutic agent cisplatin and the immunomodulator BCG have also achieved some success. In one trial, BCG was 69% effective in treating nodular and small fibroblastic sarcoids around the eye when repeatedly injected into the lesion and injection with cisplatin was 33% effective overall (mostly in horses with nodular sarcoids). However, BCG treatment carries a risk of allergic reaction in some horses and cisplatin has a tendency to leak out of sarcoids during repeated dosing. External beam radiation can also be used on small sarcoids, but is often impractical. Cisplatin electrochemotherapy (the application of an electrical field to the sarcoid after the injection of cisplatin, with the horse under general anesthesia), when used with or without prior surgery to remove the sarcoid, had a non-recurrence rate after four years of 97.9% in one retrospective study. There is a chance of sarcoid recurrence for all modalities even after apparently successful treatment. While sarcoids are not fatal, large aggressive tumors that destroy surrounding tissue can cause discomfort and loss of function and be resistant to treatment, making euthanasia justifiable in some instances. Sarcoids may be the most common skin-related reason for euthanasia.

DNA damage is considered to be the primary cause of cancer. More than 60,000 new naturally occurring DNA damages arise, on average, per human cell, per day, due to endogenous cellular processes (see article DNA damage (naturally occurring)).

Additional DNA damages can arise from exposure to exogenous agents. 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. In other examples, UV light from solar radiation causes DNA damage that is important in melanoma, helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer, and the Aspergillus metabolite, aflatoxin, is a DNA damaging agent that is causative in liver cancer.

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.

A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer. For example, individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) are at increased risk of cancer with some defects causing up to 100% lifetime chance of cancer (e.g. p53 mutations). Such germ line mutations are shown in a box at the left of the figure, with an indication of their contribution to DNA repair deficiency. 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". About 30% of sporadic cancers do have some hereditary component that is currently undefined, while the majority, or 70% of sporadic cancers, have no hereditary component.

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. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).

When expression of DNA repair genes is reduced, this causes a DNA repair deficiency. This is shown in the figure at the 4th level from the top. With a DNA repair deficiency, more DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair or in Homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.

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.

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. Men who currently smoke tobacco develop lung cancer at a rate 14 times that of men who have never smoked tobacco, so the chance of lung cancer in a current smoker being caused by smoking is about 93%; there is a 7% chance that the smoker's lung cancer was caused by radon gas or some other, non-tobacco cause. These statistical correlations have made it possible for researchers to infer that certain substances or behaviors are carcinogenic. 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 5,000 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. First, there exists a highly positive correlation (Spearman’s rho = 0.81; P < 3.5 × 10−8) between the risk of developing cancer in a tissue and the number of normal stem cell divisions taking place in that same tissue. The correlation applied to 31 cancer types and extended across five orders of magnitude. This correlation means that if the normal stem cells from a tissue divide once, the cancer risk in that tissue is approximately 1X. If they divide 1,000 times, the cancer risk is 1,000X. And if the normal stem cells from a tissue divide 100,000 times, the cancer risk in that tissue is approximately 100,000X. 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. Second, statistics show that most human cancers are diagnosed in aged people. 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.

In the United States, about 8,900 cases are diagnosed a year. The risk of testicular cancer in white men is approximately 4-5 times the risk in black men, and more than three times that of Asian American men. The risk of testicular cancer in Latinos and American Indians is between that of white and Asian men. The cause of these differences is unknown.

Most mammary tumors in rats are benign fibroadenomas, which are also the most common tumor in the rat. Less than 10 percent are adenocarcinomas. They occur in male and female rats. The tumors can be large and occur anywhere on the trunk. There is a good prognosis with surgery. Spayed rats have a decreased risk of developing mammary tumors.

There is a diverse classification scheme for the various genomic changes that may contribute to the generation of cancer cells. Many of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. There are also many epigenetic changes that alter whether genes are expressed or not expressed. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change that is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis. Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal region, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

Mammary tumors are the third most common neoplasia in cats, following lymphoid and skin cancers. The incidence of mammary tumors in cats is reduced by 91 percent in cats spayed prior to six months of age and by 86 percent in cats spayed prior to one year, according to one study. Siamese cats and Japanese breeds seem to have increased risk, and obesity also appears to be a factor in tumor development. Malignant tumors make up 80 to 96 percent of mammary tumors in cats, almost all adenocarcinomas. Male cats may also develop mammary adenocarcinoma, albeit rarely, and the clinical course is similar to female cats. As in dogs, tumor size is an important prognostic factor, although for tumors less than three centimeters the individual size is less predictive. According to one study, cats with tumors less than three cm had an average survival time of 21 months, and cats with tumors greater than three cm had an average survival of 12 months. About 10 percent of cat mammary tumors have estrogen receptors, so spaying at the time of surgery has little effect on recurrence or survival time. Metastasis tends to be to the lungs and lymph nodes, and rarely to bone. Diagnosis and treatment is similar to the dog. There is a better prognosis with bilateral radical surgery (removing the both mammary chains) than with more conservative surgery. Doxorubicin has shown some promise in treatment.

Giant-cell lung cancers have long been considered to be exceptionally aggressive malignancies that grow very rapidly and have a very poor prognosis.

Many small series have suggested that the prognosis of lung tumors with giant cells is worse than that of most other forms of non-small-cell lung cancer (NSCLC), including squamous cell carcinoma, and spindle cell carcinoma.

The overall five-year survival rate in GCCL varies between studies but is generally considered to be very low. The (US) Armed Forces Institute of Pathology has reported a figure of 10%, and in a study examining over 150,000 lung cancer cases, a figure of 11.8% was given. However, in the latter report the 11.8% figure was based on data that included spindle cell carcinoma, a variant which is generally considered to have a less dismal prognosis than GCCL. Therefore, the likely survival of "pure" GCCL is probably lower than the stated figure.

In the large 1995 database review by Travis and colleagues, giant-cell carcinoma has the third-worst prognosis among 18 histological forms of lung cancer. (Only small-cell carcinoma and large-cell carcinoma had shorter average survival.)

Most GCCL have already grown and invaded locally and/or regionally, and/or have already metastasized distantly, and are inoperable, at the time of diagnosis.