- 1. Cancer induction may require accumulation of 6–7 independent mutations over several decades, typically involving:
- a. Conversion of proto-oncogenes to oncogenes.
- b. Inactivation of tumor suppressor genes.
- 2. An example is Vogelstein’s model for a form of colorectal cancer, hereditary FAP (Figure 18.15).
- a. Mutation of both alleles of a tumor suppressor gene on chromosome 5, APC (adenomatous polyposis coli), causes increased cell growth.
- b. Hypomethylation of the DNA leads to a benign tumor (adenoma class I).
- c. Mutation of the chromosome 12 ras proto-oncogene allows cells to form a larger benign tumor (adenoma class II).
- d. If both copies of DCC, a tumor suppressor gene on chromosome 18, are lost, an even larger adenoma class III results.
- e. Mutation of both p53 alleles on chromosome 17 results in conversion to a carcinoma.
- f. Other gene losses result in the cancer metastasizing.
- g. Other paths are possible, but in all cases deletions of APC and mutations of ras occur before deletions of DCC and p53.
Fig. 18.15 A multistep molecular event model for the development of hereditary adenomatous polyposis (FAP), a colorectal cancer - Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
- 1. Carcinogens are natural and artificial agents that increase the frequency of cells becoming cancerous.
- 2. Chemicals are responsible for more human cancers than viruses.
- a. Chemical carcinogenesis was first discovered in 18th century chimney sweeps with increased incidence of scrotal cancer due to coal soot.
- b. Many present-day cancers are related to occupational exposures to carcinogens.
Chemical Carcinogens - 1. Chemical carcinogens are both natural and synthetic, and are divided into two major classes (both types of carcinogens cause point mutations):
- a. Direct-acting carcinogens bind DNA and act as mutagens. Alkylating agents are an example.
- b. Procarcinogens are metabolically converted by normal cellular enzymes to ultimate carcinogens that bind DNA and cause mutations. Most chemical carcinogens are procarcinogens. Examples include:
- i. Polycyclic aromatic hydrocarbons found in, for example, smoke from wood, coal and cigarettes.
- ii. Azo dyes.
- iii. Natural metabolites (e.g., aflatoxin from fungi).
- iv. Nitrosamines (from nitrites in food).
- 2. Chemical carcinogens are responsible for most U.S. cancer deaths, with tobacco smoke and diet responsible for 50–60%.
- a. Tobacco smoking accounts for about 30% of cancer deaths.
- b. Risk is influenced by:
- i. Amount of tobacco smoked.
- ii. Tar content of the tobacco.
- iii. Age at which smoking began (earlier increases risk).
- iv. Exposure to secondhand smoke.
- c. A major type of carcinogen in tobacco smoke is polycyclic hydrocarbons. Converted to the ultimate carcinogen derivative in the cell, they react with negatively charged molecules such as DNA, resulting in mutations.
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