A. Carcinogenesis is the process by which normal cells are transformed into malignant cells.

B. Evidence indicates that an individual cancer arises from a single cell that undergoes mutations to give it a growth and survival advantage over other cells.

1. Somatic cell mutations arise from genetic damage acquired over time that is not repaired and is allowed to alter cellular functions. These are nonfamilial and may arise without a clear risk factor.

2. Germ cell mutations arise in the DNA one inherits, and they exhibit familial tendencies.

C. It takes multiple mutations of a cell’s genes to create a malignancy. These mutations do not need to occur in any particular order but must affect specific types of genes for a malignancy to occur. Because multiple mutations over a period of time are required to develop most cancers, the risk of developing cancer increases as a person gets older.

D. There are three types of genes that can cause cancer when they develop mutations. These are the genes that regulate proliferation of cells.

1. Proto-oncogenes (eg, K-Ras)

a. These genes are responsible for promoting normal cell replication. They are necessary for maintenance of many body tissues.

b. Oncogenes are formed when proto-oncogenes are mutated. They then can overstimulate cell replication leading to continuous, uncontrolled growth and malignant transformation.

2. Tumor suppressor genes (eg, p53 gene)

a. These genes are responsible for slowing or stopping cell replication. When tumor suppressor genes become inactivated or dysfunctional, continual and uncontrolled cellular growth with malignant transformation can occur.

b. Inactivation of tumor suppressor genes may also impair the process of apoptosis (programmed cellular death), which is normally initiated in a cell that has irreparable genetic damage or has completed its normal number of replications. Lack of appropriate apoptosis is a precursor condition of malignancy.

3. DNA repair genes

a. These genes repair damage in a cell’s DNA before replication is allowed to occur. If the DNA repair genes become inactivated, mutations to the proto-oncogenes and tumor suppressor genes are allowed to accumulate and continue the cell’s transformation to malignancy.

E. Genetic mutations can be inherited but, more frequently, are errors that occur during DNA replication or after exposure to various carcinogens.

1. Inherited mutations account for a relatively small but significant percentage of cancer cases diagnosed each year. With these syndromes, a person inherits a faulty (mutated) gene that performs a function in the control of cellular replication. This mutation can significantly increase the risk of developing certain types of cancer.

a. Li-Fraumeni syndrome involves the inheritance of a defective p53 tumor suppressor gene. People with Li-Fraumeni syndrome have an increased risk of developing sarcomas, brain cancer, breast cancer, and leukemia.

b. Multiple endocrine neoplasia type II (MEN II) involves the inheritance of a mutated RET (rearranged during transfection) oncogene. This leads to a greatly increased risk of developing medullary thyroid cancer.

2. Errors occur quite frequently during cellular and DNA replication, leading to translocations, additions, or deletions of genes. If these errors occur in the genes responsible for initiating cell replication (proto-oncogenes) or for stopping cell replication (tumor suppressor genes), a cell can be allowed to divide in an uncontrolled manner. If the error occurs in the DNA repair gene, the mutations will be carried forward into future generations of cells.

3. Carcinogens are substances that can cause genetic mutations and alter cellular function.

a. Viruses can cause genetic mutations by inserting their genetic coding into the cell’s DNA. Viruses have been associated with specific types of cancers.

(1) Human papilloma virus (HPV) has been associated with cervical cancer.

(2) Hepatitis B and C viral infections increase the risk of developing hepatocellular cancer.

(3) Epstein-Barr virus has been associated with an increased risk of Burkitt’s lymphoma.

(4) Human T-cell lymphotrophic virus infection increases the risk of developing T-cell leukemia.

b. Bacteria have been implicated in the development of certain cancers. Helicobacter pylori infections have been linked to an increased risk of gastric cancer.

c. Tobacco use in all forms is considered to be the biggest contributing factor in the development of cancer.

(1) Cigarette smoking has been implicated in the development of lung, head and neck, esophageal, stomach, pancreatic, kidney, and bladder cancers.

(2) Pipes, cigars, and smokeless tobacco have been linked to lip and oral cancers.

d. Alcohol use in excessive amounts has been tied to several types of cancer, such as oral, throat, esophageal, liver, and breast cancers. The risk is especially high in people who consume both excessive amounts of alcohol and smoke cigarettes.

e. Environmental carcinogens include various forms of radiation, asbestos, pollution, and industrial compounds.

(1) Exposure to ultraviolet radiation from the sun has been linked to different forms of skin cancer.

(2) Exposure to ionizing radiation such as from radioactive chemicals or sources used in radiation therapy can increase the risk of cancers such as leukemia, thyroid and breast cancers.

(3) Exposure to asbestos has been implicated in the development of mesothelioma and other lung cancers.

(4) Pollutants in the air (eg, fluorocarbons) and water (eg, arsenic) at sufficient levels have been associated with higher incidence of lung, bladder, and skin cancer.

(5) Wood, leather, and metal dust created during refining procedures have been associated with nasal and sinus cancers.

f. Numerous chemicals are believed to have the potential to cause genetic mutations, thus increasing the risk of developing specific cancers. Examples include benzene (leukemia), vinyl chloride (sarcoma), arsenic (lung, skin, sarcoma), and the alkylating antineoplastic agents (leukemia, lymphoma).

g. Immune suppression and administration of immunosuppressive medications (eg, corticosteroids, cyclosporine, azathioprine) have been linked to development of hematologic malignancies (leukemia, lymphoma).

h. Hormones can play a role in the development and growth stimulation of several hormone-sensitive tumor types.

(1) Estrogen is known to play a role the development and growth of breast and endometrial cancers. The anti-estrogens tamoxifen and raloxifene have been shown to decrease the risk of developing breast cancer.

(2) Testosterone has been implicated in the development and growth of prostate cancer.

i. Diet can play a potentiating as well as protective role in the development of cancer. The role of diet in carcinogenesis is quite controversial.

(1) A high-fat diet has been linked to an increased incidence of colon, prostate, lung, and endometrial cancers.