Although the theme of this chapter emphasizes the genetic basis of cancer, there is no contradiction in considering the role of environment in carcinogenesis. By environment, we mean exposure to a wide variety of different types of agents— food, natural and artificial radiation, chemicals, and even viruses and bacteria that are colonizing the gut. The risk for cancer shows significant variation among different populations and even within the same population in different environments. For example, gastric cancer is almost three times as common among Japanese people in Japan as among Japanese people living in Hawaii or Los Angeles.

In some cases, environmental agents act as mutagens that cause somatic mutations; the somatic mutations, in turn, are responsible for carcinogenesis. According to some estimates based chiefly on data from the aftermath of the atomic bombings of Hiroshima and Nagasaki, as much as 75% of the risk for cancer may be environmental in origin. In other cases there appears to be a correlation between certain exposures and risk for cancer, such as the benefits of dietary fiber or low- dose aspirin therapy in lowering colon cancer risks. The nature of environ mental agents that increase or reduce the risk for cancer, the assessment of the additional risk associated with exposure, and ways of protecting the population from such hazards are matters of strong public concern.

Radiation

 Ionizing radiation is known to increase the risk for cancer. Everyone is exposed to some degree of ionizing radiation through background radiation (which varies greatly from place to place) and medical exposure. The risk is dependent on the age at exposure, being greatest for children younger than 10 years and for older adults.

Although there are still large areas of uncertainty about the magnitude of the effects of radiation (especially low- level radiation) on cancer risk, some information can be gleaned from events involving large- scale release of radiation into the environment. The data for survivors of the Hiroshima and Nagasaki atomic bombings, for example, show a long latency period, in the 5- year range for leukemia but up to 40 years for some tumors. In contrast, there has been little increase in cancer detectable among populations exposed to ionizing radiation by the more recent nuclear accident at Chernobyl, with the exception of a significant five- to sixfold increase in thyroid cancer among the most heavily exposed children living in Belarus. The increase in thyroid cancer is almost certainly caused by the radioactive iodine (131I) that was present in the nuclear material released from the damaged reactor and was taken up and concentrated within the thyroid gland.

Chemical Carcinogens

Interest in the carcinogenic effect of chemicals dates back at least to the 18th century, when the high incidence of scrotal cancer in young chimney sweeps was noticed. Today there is concern about many possible chemical carcinogens, especially tobacco, components of the diet, industrial carcinogens, and toxic wastes. Documentation of the risk of exposure is often difficult, but the level of concern is such that all clinicians should have a working knowledge of the subject and be able to distinguish between well- established facts and areas of uncertainty and debate.

The precise molecular mechanisms by which most chemical carcinogens cause cancer are still the subject of extensive research. One illustrative example of how a chemical carcinogen may contribute to the development of cancer is that of hepatocellular carcinoma, the fifth most common cancer worldwide. In many parts of the world, hepatocellular carcinoma occurs at increased frequency because of ingestion of aflatoxin B1, a potent carcinogen produced by a mold found on peanuts. Aflatoxin has been shown to mutate a particular base in the TP53 gene, causing a G to T mutation in codon 249, thus converting an arginine codon to serine in the critically important p53 protein. This mutation is found in nearly half of all hepatocellular carcinomas in patients from parts of the world in which there is a high frequency of contamination of food by aflatoxin, but it is not found in similar cancers in patients whose exposure to aflatoxin in food is low. The p.Arg249Ser variant in p53 enhances hepatocyte growth and interferes with the growth control and apoptosis associated with wild- type p53; LOH of TP53 in hepatocellular carcinoma is associated with a more malignant appearance of the cancer. Although aflatoxin B1 alone is capable of causing hepatocellular carcinoma, it can also act synergistically with chronic hepatitis B and C infections.

A more complicated situation occurs with an exposure to complex mixtures of chemicals, such as the many known or suspected carcinogens and mutagens found in cigarette smoke. The epidemiologic evidence is overwhelming that cigarette smoke increases the risk for lung cancer and throat cancer, as well as other cancers. Cigarette smoke contains polycyclic hydrocarbons that are converted to highly reactive epoxides that cause mutations by directly damaging DNA. The relative importance of these substances and how they might interact in carcinogenesis are still being elucidated.

The case of cigarette smoking also raises another interesting issue. Why do only some cigarette smokers get lung cancer? Increasingly heritable underpinnings are becoming understood. The association between cancer and cigarette smoking provides an important example of the interaction between environmental and genetic factors to either enhance or prevent the carcinogenic effects of chemicals. The enzyme aryl hydrocarbon hydroxylase (AHH) is an inducible protein involved in the metabolism of polycyclic hydrocarbons, such as those found in cigarette smoke. AHH converts hydrocar bons into an epoxide form that is more easily excreted by the body but is also carcinogenic. AHH activity is encoded by members of the CYP1 family of cytochrome P450 genes. The CYP1A1 gene is inducible by cigarette smoke, but the inducibility is variable in the population because of different common variants at the CYP1A1 locus. People who carry a high- inducibility variant, particularly those who are smokers, appear to be at an increased risk for lung cancer, with odds ratios of 4 to 5 compared to individuals without the cancer- susceptibility CYP1A1 variant. On the other hand, homozygotes for the recessive low- inducibility variant appear to be less likely to develop lung cancer, possibly because their AHH is less effective at converting the hydrocarbons to highly reactive carcinogens.

Similarly, individuals homozygous for common variants in the CYP2D6 gene that reduce the activity of another cytochrome P450 enzyme appear to be more resistant to the potential carcinogenic effects of cigarette smoke or occupational lung carcinogens (e.g., asbestos or polycyclic aromatic hydrocarbons). Normal or ultrafast metabolizers, on the other hand, who carry variants that increase the activity of the Cyp2D6 enzyme, have a fourfold greater risk for lung cancer than do slow metabolizers. This risk increases to 18- fold among persons exposed routinely to lung carcinogens. A similar association has been reported for bladder cancer.

Although the precise genetic and biochemical basis for the apparent differences in cancer susceptibility within the normal population remains to be determined, these associations could have significant public health consequences and may point eventually to a way of identifying persons who are genetically at a higher risk for the development of cancer.

اخر الاخبار

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المزيد

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للطاقة وحماية القلب.. ما "التوقيت الذهبي" لأكل المكسرات؟

دراسة تكشف فائدة القيلولة لمدة 45 دقيقة

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هل يعدّ الصيام المتقطع حلا سحريا لخسارة الوزن؟.. دراسة تجيب

المزيد

الآخبار التكنلوجية

"علي بابا" تكشف عن نموذج جديد للذكاء الاصطناعي

اختراق علمي جديد.. استشعار ضوئي يرصد "دلالات السرطان"

وكالة الإمارات للفضاء تعلن تمديد مهمة "مسبار الأمل" حتى 2028

ظاهرة مذهلة .. شهدها 2 بالمئة من سكان العالم فقط

المزيد

مواضيع ذات صلة

Cytogenetic Changes in Cancer

Telomerase as an Oncogene

Activation of Oncogenes by Chromosome Translocation or Fusions

Imaging of the Pituitary: Adenomas

T pit Family of tumours

Pit- 1 Family of tumours

Pituitary Adenomas

Molecular Mechanisms of Carcinogenesis

Chronic Myeloid Leukemia, BCR-ABL Gene, and Disease Monitoring

Application of Liquid Biopsy to Non-small- Cell Lung Cancer Lung

Circulating Tumor DNA

Biomarkers in the Blood and in Tissues: A Complementary Approach