Cancer really refers to a disease with more than 100 different forms -- almost every tissue can give rise to cancerous cells and malignancies.

Three classes of genes now appear to play the major roles in triggering cancer:

1. overproduction of growth factors;
2. flooding of the cell with replication signals;
3. uncontrolled stimulation in the intermediary pathways; and/or
4. unrestrained cell growth driven by elevated levels of transcription factors.

The activation of a proto-oncogene to express its oncogenic potential can occur in several ways:

• point mutation
• chromosome rearrangement
• gene amplification... an increase in the number of copies of a normal proto-oncogene within a cell
• viral insertion resulting in control of a proto-oncogene by a more active promotor

Examples of Oncogenes

• erb-B - codes for a receptor for epidermal growth factor involved in glioblastoma, a brain cancer, and breast cancer
• erb-B2 - also called HER-2 or neu, involved in breast, ovarian, and salivary gland cancers
• Ki-ras - codes for a protein that relays a stimulatory signal involved in lung, ovarian, colon, and pancreatic cancers
• N-ras - involved in leukemias
• c-Myc, N-myc, L-myc - all genes for transcription factors that activate growth promoting genes involved in leukemias, breast, stomach, and lung cancers (c-Myc, L-myc); neuroblastoma (N-myc)
• Bcl-1 - codes for cyclin D1, a component of the cell cycle clock involved in breast, head and neck cancers

• normally function to inhibit or put the brakes on the cell growth and division cycle; they function to prevent the development of neoplasia. Mutations in tumor suppressor genes cause the cell to ignore one or more of the components of the network of inhibitory signals,
• removing the brakes from the cell cycle and resulting in a higher rate of uncontrolled growth -- cancer.
• In a manner similar to oncogenes, the products of tumor suppressor genes function in all parts of the cell...... at the cell surface, in the cytoplasm, and in the nucleus.
• These genes are defined by the impact of their absence and thus tend to be recessive -- both normal alleles must mutate before cancerous growth begins. Thus, neoplasia is the result of a loss of function. The loss or inactivation of a normal tumor suppressor gene may be acquired somatically in a single clone of cells or be constitutionally present throughout the body including the germ line.
• It has been hypothesized that the development of tumors requires two separate mutational events. One of these events may occur in the germline and be inherited; the second then occurs somatically. Alternatively, the two mutational events may occur only in the somatic cell of an individual. This "two hit hypothesis" has helped to explain the natural history of retinoblastoma and has been extended to other tumors.

• One tumor suppressor locus is usually involved in controlling the development of several different kinds of tumors.
• Tumor suppressor genes tend to be evolutionarily conserved.
• Tumor suppressor genes are often associated with the loss of one chromosome or a part of a chromosome, resulting in a reduction to homozygosity through elimination of one allele of a tumor suppressor gene as well as surrounding markers; the remaining tumor suppressor allele is either inactivated by an inherited or a somatic mutation.

• DPC-4 - involved in pancreatic cancer; participates in a cytoplasmic pathway that inhibits cell division
• NF-1 - involved in neurofibromas and pheochromocytomas of the nervous system and myeloid leukemia codes for a protein that inhibits Ras, a cytoplasmic inhibitory protein
• NF-2 - involved in meningioma, schwannoma, and ependymoma of the nervous system - codes for a nuclear protein
• RB - involved in retinoblastoma as well as bone, bladder, small cell lung, and breast cancers codes of the pRB protein, a nuclear protein that is a major brake in the cell cycle.
• p53 - involved in a wide range of tumors inactive or lost in more than 50% of cancerous cells codes for the cytoplasmic p53 protein that regulates cell division and can induce cells to kill themselves ("apoptosis")
• WT1 - involved in Wilms tumor of the kidneys
• BRCA1 - involved in breast and ovarian cancer
• BRCA2 - involved in breast cancer

In addition to proto-oncogenes and tumor suppressor genes, a third group of cancer causing genes are emerging as sources of cancer -- DNA repair genes. These are genes that ensure each strand of genetic information is accurately copied during cell division of the cell cycle.

• Mutations in DNA repair genes lead to an increase in the frequency of other mutations.
• These may result in cells with fragile chromosomes, broken and/or fragmented chromosomes.

Disorders include:

• Bloom's syndrome
• ataxia-telangiectasia
• Fanconi anemia
• xeroderma pigmentosum
• hereditary nonpolyposis colon cancer (HNPCC)