Risk Factors and Cancer

Cancer is a multifactorial disease, in which both environmental and genetic factors play a role. Part of the environmental factors are conditions of life that result in exposures to carcinogens depending on where people live and work as well as changes that people make in the world. Cancer shows both geographic and temporal variability, and there are different patterns of cancer at different places and different times which depend both on lifestyle and habits as well as environmental hazards.15 Risk factors in cancer etiology comprise four classes of external agents in carcinogenesis (carcinogens): physical, chemical and biological agents, and diet.12'13'15

The increasing knowledge of the process of carcinogenesis induced by chemical agents provides a major basis for cancer control and has unraveled the association between smoking and lung cancer. About 30% of all cancer deaths in the USA are due to the use of tobacco, and this death toll is still increasing reflecting smoking habits among young women since the 1950s.1,15 Smoking causes more than 90% of all cases of lung cancer and is the main cause of cancers of the larynx, mouth, esophagus, bladder, kidney, and pancreas, while about 25% of colon cancer and polyps can be attributed to smoking. Five years after stopping smoking, the risk of cancer decreases to half and to the level of lifelong nonsmokers after 10-15 years. Reducing the epidemic of tobacco smoking is currently the most effective means of cancer prevention.15-17

Diet and obesity in adults account for 30% of all cancer deaths in the USA. Diet has been shown to play a significant role in the causation of cancer but little is known about how it plays its role as a carcinogen.15,18 Excessive fat in the diet raises the risk of colorectal and breast cancer and possibly prostate cancer. Adult obesity is associated with endometrial cancer, postmenopausal breast cancer, and cancers of the colon, rectum, and kidney.15,18 Obesity in concert with other risk factors such as low activity level, menopausal status, and predisposition to insulin resistance significantly increase the risk of cancer. While some methods of food preparation and preservation have been shown to increase the risk of various forms of cancers, certain classes of foods appear to contain protective substances against cancer including vegetables, whole grain products (fiber), and citrus fruits.12,15,18,20 Salt intake has been associated with risk of stomach cancer, but no other food additive or contaminant (except for aflatoxins)21 has been linked conclusively to cancer. Therefore, a diet that reduces cancer risk has been proposed.12,15,18,20

Occupational factors may account for 5% of all cancer deaths, and these include mostly cancers of the lung, bladder, and bone marrow.1,19 Workplace exposure, the most important carcinogen, which can increase the rate of cancer by 10 to 100 times the rate in unexposed people, is second to tobacco smoke.16,17,19 About 15% of lung cancers and about 10% of skin and bladder cancers are caused by workplace exposure.

A family history of cancer is also an important risk factor and can increase the risk of cancers of the breast, colon, prostate, and lung by 1.5-3-fold accounting for perhaps 5% of all cancer deaths in the USA. Susceptibility to cancer is due to genetic mutations of key regulatory genes that occur in the germline.9,23 About 5-10% of most types of cancer are due to defects in single genes that run in families. Cancer incidence also depends on genetic polymorphisms that affect the absorption, transport, metabolic activation, or detoxification of environmental carcinogens and may act as cancer-facilitating influences.19'24

Both DNA and RNA viruses are responsible for about 5% of human cancer but are a more common causes of cancer in animals where they play a central role in the identification of oncogenes.25'26 About 5% of adult T cell leukemias/lymphomas are due to human lymphotropic virus type I27 while Epstein-Barr virus accounts for 10-15% of non-Hodgkin's lymphoma, Burkitt's lymphoma (almost all children in central Africa and 20% of cases occurring elsewhere), 35-50% of Hodgkin's disease, and 40-70% of nasopharyngeal carcinoma (especially in southern Chinese).28 Hepatitis B virus accounts for 40-60% of hepatocellular carcinoma and hepatitis C virus for 20-30%.29 Some subtypes of the human papilloma viruses (HPV16 and HPV18) account for 90% of cervical cancer. HPV infection is now recognized to be a sexually transmitted disease with special risk from early sexual exposure before the cervix is fully mature. HPV viruses cause benign warts and may be involved in cancers of the oral cavity and upper respiratory tract.30 The developing countries bear the greatest impact from these cancers from very early infections with these agents.

Establishment of latent and chronic infections with associated higher levels of viral replication31-33 increases the probability of causing secondary genetic damage to target tissues with associated immune dysfunction contributing to carcinogenesis.

Reproductive factors associated with hormonal changes such as early age at menarche, late age at first birth, late age at menopause, and nulliparity each increase the risk of breast cancer. Nulliparity is also associated with endo-

metrial and ovarian cancers. Early age at first intercourse increases the risk of cervical cancer, more likely through HPV



Alcohol and tobacco smoking are the main cause of cancers of the upper respiratory and gastrointestinal tracts. Alcohol by itself plays a role in liver cancer (cirrhosis) and possibly in a proportion of colon and breast cancer.36 Poverty is associated with increased exposure to tobacco smoke, alcoholism, poor nutrition, and certain infectious agents. Thus, poverty can act as a carcinogen, which suggests that fighting cancer also requires fighting poverty.

Surprisingly, the contribution of air pollution in causing lung cancer is less than anticipated (1% of lung cancer deaths yearly in the USA with a higher risk for urban smokers compared with rural smokers).37 Risks associated with environmental exposures are several orders of magnitude less than that associated with smoking. Aromatic organochlorines dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) accumulate along the food chain in fatty tissues and can bind to estrogen receptors causing estrogenic or antiestrogenic effects in animals.

Over 90% of melanomas, basal cell carcinomas, and squamous cell carcinomas are due to sunlight exposure.38 Most skin cancers are nonmelanoma skin cancers and account for 40% of all new cancers in the USA yearly. Although the major DNA-damaging spectrum is ultraviolet (UV)-B radiation the excessive exposure to the UVA-ray as used in sun lamps and sun bed can also cause DNA damage.19,24,38

Ionizing radiation is a universal but weak carcinogen.1,39 However, cumulative exposures from medical diagnostic and treatment procedures, commercial, occupational sources, or waste increase the risk of cancer. Leukemias and cancers of the breast, lung, and thyroid are typical but cancers of the stomach, colon, and bladder, and potentially any human tumor may be seen. Radiation can cause most types of cancer, especially myelogenous leukemia and cancers of the breast, thyroid, and lung. Some cancers that have not been linked to radiation include chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, and cancers of the cervix, testis, prostate, and pancreas. Despite the massive radiation contamination resulting from the nuclear reactor accidents at Chernobyl and Chelyabinsk thus far the only well-documented increase in cancer is childhood thyroid cancer.40 Finally, genetic predisposition can increase the risk of developing cancer by exposure to radiation, as in the cases of inherited retinoblastoma (bone tumors) and hereditary ataxia telangiectasis (lymphoid tumors).41-43

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