The incidence of cancer has been correlated with certain environmental factors. Table 33-1 lists environmental factors that have been definitively linked with cancer, including aerosol and industrial pollutants, drugs, and infectious agents. Radiation exposure is also known to be associated with specific types of cancer (e.g., acute leukemia, thyroid cancer, sarcomas, breast cancer). Women concerned about organochlorine substances (e.g., polychlorinated biphenyls [PCBs], dioxins, pesticides [DDT, banned in 1972]) can be reassured that available evidence does not suggest an association between exposure to these chemicals and breast cancer.

Table 33-1

Selected Environmental Factors Associated With Cancer

Factor	Type of Cancer
Aerosol and Industrial Pollutants
Asbestos (silica)	Mesothelioma
Lead, copper, zinc, arsenic, cyclic aromatics, tobacco	Lung cancer
Vinyl chloride	Liver angiosarcoma
Benzene	Leukemia
Aniline dyes, coal	Skin and bladder carcinoma
Drugs
Androgenic steroids	Hepatocellular carcinoma
Stilbestrol (prenatal)	Vaginal adenocarcinoma
Estrogen (postmenopausal)	Endometrial carcinoma
Hydantoins	Lymphoma
Chloramphenicol, alkylating agents	Leukemias, lymphomas
Infectious Agents
Epstein-Barr virus	Burkitt’s lymphoma, nasopharyngeal cancer (?) Hodgkin’s disease
Human papillomavirus	Cervical cancer
Herpesvirus type 2	Cervical cancer
Human immunodeficiency virus (HTLV-III)	Kaposi’s sarcoma, non-Hodgkin’s lymphoma, primary lymphoma of the brain, bladder cancer
HTLV-I	Non-Hodgkin’s lymphoma
Hepatitis B	Hepatocellular carcinoma

Most chemical carcinogens are inactive in their native state and must be activated by enzymes in the cytochrome P-450 or other enzyme systems (e.g., bacterial enzymes or enzymes induced by alcohol).

In radiation carcinogenesis, ionizing particles (e.g., alpha and beta particles, gamma rays, x-rays) hydrolyze water into free radicals, which are mutagenic to DNA by activating proto-oncogenes. Ultraviolet (UV) light, especially UVB, induces the formation of thymidine dimers, which distort the DNA molecule, leading to skin cancers (e.g., basal cell carcinoma, malignant melanoma).

Host Factors and Disease Associations

Various host factors have been linked to a higher than expected incidence of cancer. For example, the presence of certain genetic disorders (e.g., Down syndrome) is associated with an increased incidence of leukemia. The link between certain genetic abnormalities and leukemia is consistent with a germinal or somatic mutation in a stem cell line.

Familial clustering of germ cell tumors, malignant tumors arising in the testis, has been observed, particularly among siblings. Cryptorchidism and Klinefelter’s syndrome are predisposing factors in the development of germ cell tumors arising from the testis and mediastinum, respectively.

The incidence of cancer is 10,000 times greater than expected in patients with an immunodeficiency syndrome. The increased incidence of lymphomas in congenital, acquired, and drug-induced immunosuppression is consistent with the failure of normal immune mechanisms or antigen overstimulation with a loss of normal feedback control. Table 33-2 lists other cancer-related conditions.

Table 33-2

Cancer-Related Conditions

Disease	Related Cancer
Paget’s disease	Osteogenic sarcoma
Cryptorchidism	Testicular cancer
Neurofibromatosis	Brain tumors, sarcoma
Esophageal webbing	Esophageal carcinoma
Achlorhydria and pernicious anemia	Gastric carcinoma
Cirrhosis	Hepatoma
Cholelithiasis	Gallbladder cancer
Chronic inflammatory bowel disease	Colon cancer
Migratory thrombophlebitis	Adenocarcinoma, especially pancreatic
Myasthenia gravis, pure red cell aplasia, T cell disorder	Thymoma
Nephrotic syndrome	Membranous carcinomas; lymphomas, especially Hodgkin’s

Viruses

Viral causes of some cancers are known. Viruses associated with specific cancers are listed in Table 33-1. Nonpermissive cells that prevent an oncogenic RNA or DNA virus from completing its replication cycle often produce changes in the genome that result in the activation of proto-oncogenes or inactivation of suppressor genes.

Stages of Carcinogenesis

Some precancerous conditions progress through a series of growth alterations before becoming cancerous. For example, cervical cancer progresses from squamous metaplasia to squamous dysplasia to carcinoma in situ, and finally to invasive cancer. Endometrial cancer progresses from endometrial hyperplasia to atypical endometrial hyperplasia to carcinoma in situ, and finally to invasive cancer.

Cancer (Box 33-1) results from a series of genetic alterations that can include the following:

Box 33-1 The Process of Cancer

Cancer is a multistep process involving the following:

• Initiation (irreversible mutations involving proto-oncogenes)

• Promotion (growth enhancement to pass on the mutation to other cells)

• Progression (e.g., development of tumor heterogeneity for metastasis, drug resistance)

• Activation of oncogenes that promote cell growth

• Loss of tumor suppressor gene activity, which inhibits cell growth

Mutation or overexpression of oncogenes produces proteins that can stimulate uncontrolled cell growth, whereas mutation or deletion of tumor suppressor genes results in the production of nonfunctional proteins that can no longer control cell proliferation. The mutant cell multiplies and the succeeding generations of cells aggregate to form a malignant tumor.

Interleukin-24 (IL-24), initially called MOB-5, is a protein that is usually secreted by immune system cells in response to injury or infection. Research on colon cancer cells has demonstrated that IL-24, in conjunction with its receptors, appears to give a cancer cell the ability to fuel its own growth. The secreted proteins are released from one cell to transmit a signal to grow, migrate, or survive to another cell. These proteins cannot act alone and must act through a receptor or receptors on the receiving cell.

Cancer-Predisposing Genes

Cancer-predisposing genes may act in the following ways:

• Affect the rate at which exogenous precarcinogens are metabolized to actively carcinogenic forms that can damage the cellular genome directly

• Affect a host’s ability to repair resulting damage to DNA

• Alter the immune ability of the body to recognize and eradicate incipient tumors

• Affect the function of the apparatus responsible for the regulation of normal cell growth and associated proliferation of tissue

Relatively few cancer-predisposing genes have been described. An absence of functional alleles at specific loci, however, allows the genesis of the malignant process (Table 33-3). For example, individuals with certain mutations in the gene BRCA2 are at a very high risk (up to 85%) for developing breast cancer and other cancers (e.g., ovarian cancer) because a DNA repair path cannot properly repair ongoing wear and tear to the DNA.

Table 33-3

Tumors Associated With Homozygous Loss of Specific Chromosomal Loci

Tumor Type	Chromosomal Linkage
Multiple endocrine neoplasia, type 2	1
Renal cell carcinoma	3
Lung carcinoma	3
Colon carcinoma, familial polyposis	5
Multiple endocrine neoplasia, type 2a	10
Wilms’ tumor, hepatoblastoma, rhabdomyosarcoma	11
Retinoblastoma	13
Ductal breast carcinoma	13
Colon carcinoma	17
Acoustic neuroma, meningioma	22

A mutation in a gene thought to be responsible for colon cancer may initially cause it. This gene, APC, normally limits the expression of a protein, survivin. When APC is altered, survivin works overtime and, instead of dying, stem cells in the colon overpopulate, resulting in cancer. Survivin is overexpressed in colon cancer. It prevents programmed cell death, or apoptosis, the process whereby cells normally die. Rather than dying on schedule, cancer cells instead grow out of control. The APC gene controls the amount of survivin by shutting down its production.

Proto-Oncogenes

Proto-oncogenes act as central regulators of the growth in normal cells that code for proteins involved in growth and repair processes in the body. Proteins such as growth factors or transcription factors are necessary for normal growth.

Genetic mutations in proto-oncogenes produce oncogenes. Oncogene activation causes the overexpression of growth-promoting proteins, resulting in hypercellular proliferation and tumorigenesis. Tumor suppressor genes normally counteract proto-oncogenes by encoding proteins that prevent cellular differentiation. When mutations in tumor suppressor genes cause loss of function, the expressed tumor suppressor proteins are no longer able to suppress cellular growth.

For example, the activation of proto-oncogenes (e.g., ras) involved in the growth process or inactivation of suppressor genes (e.g., p53), which keeps growth in check by binding and activating genes that put the brakes on cell division, is responsible for neoplastic transformation of a cell. Defects in the gene for p53 cause about 50% of all cancers.

p53 Protein

The p53 gene (tumor suppressor gene) is located on chromosome 17 and produces a protein that downregulates the cell cycle. A mutation of p53 is associated with an increased incidence of many types of cancer. The p53 tumor suppressor protein is dysfunctional in most human cancers. Even when p53 is not itself mutant, its regulators (e.g., p14^ARF, a p53-stabilizing protein) are often altered. The p53 protein is a key responder to various stresses, including DNA damage, hypoxia, and cell cycle aberrations. Specific molecular pathways that activate p53 depend on the nature of the stress and the cell type. Consequently, these determine the specific downstream effectors and cellular response—apoptosis, growth arrest, or senescence.

It is widely believed that the central role of p53 in tumor suppression is to mediate the response to DNA damage. If p53 is missing when damage occurs, cells do not undergo p53-mediated arrest or apoptosis. Cells that have sustained mutations in oncogenes or tumor suppressor genes because of the damage obtain a growth advantage that fuels the development of cancer.

Apparently, DNA damage itself is not the critical event that leads to cancer, as long as the oncogenic stress pathways that activate p53 are intact. For any given cancer type, p53 dysfunction generally correlates with poor treatment response and poor prognosis; therefore, restoration of p53 function is a potential avenue for therapeutic development. Drugs currently being developed will enhance the function of kinases that activate p53 in response to DNA damage.

Role of Oncogenes

The genetic targets of carcinogens are oncogenes. Oncogenes have been associated with various tumor types (e.g., HER-2/neu with breast, kidney, and ovarian cancers). Oncogenes are considered altered versions of normal genes. Over a lifetime, a variety of mutations can convert a normal gene into a malignant oncogene.

Once an oncogene is activated by mutation, it promotes excessive or inappropriate cell proliferation. Oncogenes have been detected in about 15% to 20% of a variety of human tumors and appear to be responsible for specifying many of the malignant traits of these cells. More than 30 distinct oncogenes, some of which are associated with specific tumor types, have been identified (Table 33-4). Each gene has the ability to evoke many of the phenotypes characteristic of cancer cells.

Table 33-4

Some Oncogenes Formed by Somatic Mutation of Normal Genetic Loci

Oncogene	Disorder
ab1	Chronic myelogenous leukemia
myc	Burkitt’s lymphoma
N-myc	Neuroblastoma
EGFR, HER2	Mammary carcinoma
Ras type	Wide variety of tumors

EGFR, Epidermal growth factor receptor; HER2, human EGFR-2.

Major classes of oncogene products involved in the normal growth process of cells include the following:

• Growth factors (e.g., sis oncogene)

• Epidermal growth factor receptors (EGFRs)

• Membrane-associated protein kinases (e.g., src oncogene)

• Cytoplasmic protein kinases (e.g., ras oncogene)

• Transcription regulators located in the nucleus (e.g., c-myc oncogene)

In addition, tumor suppressor genes (antioncogenes) are guardians of unregulated cell growth (e.g., p53, Rb oncogenes).

Mechanisms of Activation

Point mutations, translocations (e.g., t8;142 in Burkitt’s lymphoma) and gene amplification (multiple copies of the gene with overexpression of products) are mechanisms of activation, as follows:

• Overexpression of the c-erbB-2 (HER2/neu) oncogene is noted in up to 34% of patients with invasive ductal breast carcinoma and predicts poor survival.

• Activation of the ras proto-oncogene (point mutation) is associated with about 30% of all human cancers. About 25% of patients with acute myelogenous leukemia display this point mutation. Ras is mutated frequently in colon and pancreatic cancers; it appears that ras activation leads to unregulated expression of IL-24 and its receptors.

• Translocation of the abl proto-oncogene from chromosome 9 to chromosome 22 with formation of a large bcr-abl hybrid gene on chromosome 22 (Philadelphia chromosome) results in chronic myelogenous leukemia.

• Inactivation of suppressor genes (point mutations) leads to unrestricted cell division, inactivation of each of the RB1 suppressor genes on chromosome 13 is associated with malignant retinoblastoma in children, and inactivation of the p53 suppressor gene on chromosome 17 accounts for 25% to 50% of all malignancies involving the colon, breast, lung, and central nervous system.

Viral Oncogenes

Various RNA and DNA viruses have been associated with human malignancies (Box 33-2). Some viral agents have a clear causative role, such as the Epstein-Barr virus and certain papillomaviruses, which are the causative agents in Burkitt’s lymphoma and cervical carcinoma, respectively.

Box 33-2 Oncogenic Viruses

• Ribonucleic acid (RNA)—leukemia, carcinoma viruses, mammary tumor viruses

• Deoxyribonucleic acid (DNA)—herpesviruses, adenoviruses, papilloma viruses

Viruses carry viral oncogenes into target cells, where they become firmly established. Clonal descendants then carry the viral genes, which maintain the malignant phenotype of the cell clones.