Environmental Factors Influencing LOH

Mechanisms by which LOH occurs are varied (see Fig. 11.1), and all have been associated with at least one type of cancer. Environmental factors can contribute to LOH and have been linked to certain cancers. Carcinogenic compounds in the air we breathe, the food we eat, and even some prescription drugs can induce mutation either directly or through metabolic by-products.24 Pathogens have also been shown to play a contributing role in cancer progression.25,26

LOH is a downstream event that happens some time after exposure to a carcinogen. The initial effect is usually a small change at the single nucleotide level. Carcinogens cause mutations through highly reactive intermediate compounds produced by the metabolic or elimination processes of the body - either in the digestive tract or by immune system surveillance. These compounds can chemically react with DNA, modifying its structure. These so-called DNA adducts occur in multiple forms, depending on the chemical and molecular structure of the carcinogen.27,28 Some DNA adducts cause DNA polymerases to insert an incorrect nucleotide during DNA replication. Other DNA adducts link DNA strands to proteins or other DNA molecules, causing a physical barrier to replication.29 Other carcinogens cause DNA strand breaks.28

The body has mechanisms that monitor and repair DNA or initiate the death of cells that harbor deleterious mutations. However, chronic or high-level exposures to a carcinogen can overwhelm the body's intrinsic repair mechanisms. Some individuals inherit DNA repair-associated alleles that make them more30 or less31 susceptible to disease from many sources of mutation, including environmental carcinogens.32 In most cases, disease emerges months or years after an exposure event. Therefore, establishing linkages between environmental factors and cancers can take many years of research with large study populations.

Tobacco

Exposures to tobacco smoke from cigarette use and tobacco in smokeless products have both been linked to increased risk of cancer.33 Lung cancer is the most well known association, but tobacco smoking is a major cause of bladder cancer as well. The evidence linking exposure to tobacco smoke and lung cancer is overwhelming, with smoking named as the greatest etiological factor contributing to an individual's risk of developing lung cancer.34-37 The mechanisms by which tobacco carcinogens contribute to the development and progression of lung cancer are multivariate and are only partially understood. Tobacco smoke produces reactive chemical species, including benzo[a]pyrenes and polycyclic aromatic hydrocarbons (PAH). Smokeless tobacco is a major source of nitrosamines and is linked to increased risk of oral, esophageal, and pancreatic cancers.33

When adolescents smoke, it is believed that normal lung epithelium is "preconditioned" by exposure to tobacco carcinogens at a time of critical lung development, resulting in somatic mutations in an entire "field" of epithelium rather than in a single cell or cluster of cells.27 These genetically altered cells are replicated during normal adolescent lung growth, leading to the presence of a large number of cells that are "primed" for subsequent events (such as allelic loss), thus rendering the individual highly susceptible to the development of lung cancer. Smoking during adolescence may increase the risk that if lung cancer develops it will develop as many clonal cancers that progress concomitantly and aggressively, a concept first described as "field cancerization."37,38

Asbestos

Asbestos is a well-known pulmonary carcinogen, linked in particular to the formation of mesotheliomas, lung tumors that usually develop in individuals with a history of asbestos exposure, typically with a long period of latency between exposure and clinical presentation.39 The specific mechanisms by which asbestos contributes to LOH are not known. Mutagenicity studies carried out using a lymphocyte model demonstrated that the LOH rate upon exposure to asbestos fibers was greater than the spontaneous LOH rate of the assay,40 suggesting a direct connection between the fibers and LOH. In patients exposed to asbestos, allelic deletion of the FHIT gene on chromosome 3p1441 and LOH on regions of chromosome 6p42 have been reported, showing a correlation between asbestos exposure and LOH in human disease.

Carcinogens in Food

Food is another source of carcinogens that lead to LOH and disease. Aflatoxin, a metabolite of certain fungi, can be introduced into food sources by grains such as corn and livestock feed. Aflatoxins often occur in crops in the field before harvest. Postharvest contamination can occur if crop drying is delayed and during storage of the crop if water is allowed to exceed critical values for mold growth. Insect or rodent infestations facilitate mold invasion of some stored commodities.

Whether sodium nitrate and sodium nitrate, used to preserve meats, are carcinogens has been a matter of debate.

Chemically, the possibility exists for these compounds to be converted into nitrosoamines, which have been demonstrated as participating in the carcinogenesis resulting from tobacco smoke exposure. However, regulations on maximal levels imposed by the FDA and USDA and changes in industry processes have lowered the risk of cancer from dietary intake of preserved meats.43 Despite the lower risk of exposure from preserved meats, nitrosamines can be generated from the digestion of meats that have been charred during cooking and are ingested with smokeless tobacco products, as noted above.

Alcohol

Alcoholic beverage consumption was first added as a known human carcinogen to the U.S. Department of Health and Human Services biannual Report on Carcinogens in 2000 because it was demonstrated to increase the risk of upper gastrointestinal tract cancers (e.g., mouth, pharynx, larynx, and esophagus)44 and because evidence of a linkage to pancreatic cancer is accumulating.45 The formation of acetalde-hyde seems to be the most important mechanism by which alcoholic beverage consumption causes human cancer.27 Although the ^2-ethyl-2'-deoxyguanosine DNA adduct is increased in white blood cells obtained from human alcohol abusers, a more likely cause of the mutagenic effects of alcohol is a different DNA adduct, 1,^2-propano-2'-deoxyguanosine (PdG), that can form when acetaldehyde is in the presence of histones and other basic molecules. PdG has been shown to be responsible for the genotoxic and mutagenic effects of crotonaldehyde through the formation of secondary lesions, including DNA-protein cross-links and DNA interstrand cross-links. Individuals who smoke tobacco and are heavy consumers of alcoholic beverages are at even greater risk of upper gastrointestinal cancers than individuals who are exposed to either substance alone.

Pathogens

Inflammation associated with chronic infection can be a contributing risk factor for carcinogenesis. Examples include infection of the gastric wall with Helicobacter pylori as a predisposing factor for gastric cancer26; chronic infections of hepatitis virus leading to hepatocellular carcinoma (HCC); and the linkage of lung cancer with chronic Chlamydia pneumoniae and Mycobacterium tuberculosis (M-TB) infections.25,46 Studies indicate that the mechanism of DNA damage in relation to infections is indirect and comes from the host's activated inflammatory cells sent to fight the infection. Cumulative evidence suggests that free radicals, such as NO, produced by activated inflammatory cells can contribute to cancer, as they are known to be able to cause direct damage to DNA.47

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