Carcinogenesis Health Article

Cancer genes

Oncogenes

Normal cell proliferation is controlled by growth factors and cytokines (mediating proteins) that act on the cell membrane, triggering a cascade of biochemical signals (a process called signal transduction). These signals control, among others, the genes that regulate cell growth and division. Oncogenes are altered forms of normal cellular genes called proto-oncogenes that are involved in this cascade of events. They may mutate spontaneously, through interaction with viruses, or by chemical or physical means.

When a proto-oncogene is altered to become an oncogene, the pathway of cell growth and proliferation become altered. This may lead to the abnormal growth of cells (neoplastic transformation). More than 100 oncogenes have been identified. An example of an oncogene is the K-ras gene that is mutated in colon cancer cells.

Genes are the means by which a cell produces proteins, each of which have a very specific role. A mutated gene can cause overproduction of a protein, underproduction of a protein, or alteration of a protein that may be unable to carry out its purpose. Oncogenes typically produce more of their protein product when mutated, while tumor suppressor genes typically produce less of their protein product when mutated.

Tumor suppressor genes

Both the activation of oncogenes and the inactivation of tumor suppressor genes appear to be necessary for cancer to occur. Tumor suppressor genes are typically associated with cell growth and differentiation and cell suicide (apoptosis). More than a dozen tumor suppressor genes have been identified. Proteins produced by tumor suppressor genes typically inhibit a cell from reproducing during times when growth is inappropriate such as during DNA repair; they are considered the "brakes" of the cell.

Mutations that inactivate the tumor suppressor gene p53 are the most common mutations seen in human cancers, accounting for about 50%. Carcinomas of the breast, colon, stomach, bladder and testis; melanoma; and soft tissue sarcoma all are linked to p53 mutations. The p53 protein is found in the nucleus of the cell and regulates cell functions such as cell growth, DNA repair, and apoptosis. The most notable role for p53 is to halt cell growth to allow the cell time to repair damaged DNA. If p53 is mutated, it loses this function, apoptosis does not occur, and unregulated cell growth results. In Li-Fraumeni syndrome a mutation of the p53 gene is inherited. This puts the individual at a high risk for a number of cancers such as early onset breast carcinoma, childhood sarcomas, and other tumors. Other tumor suppressor genes include the retinoblastoma gene and the DCC gene that is mutated in colon cancer.

DNA mismatch-repair genes

This more recently discovered class of cancer susceptibility genes is associated with the genetic instability of cancer cells that allows for multiple mutations to occur. This instability hastens the course of cancer. The normal function of these genes is to repair damage to the DNA. Mutations in DNA mismatch-repair genes are most notable in hereditary non-polyposis colorectal cancer (HNPCC).

Apoptosis

—A process of cell death performed by a damaged cell.

Colon carcinogenesis

Colon cancer has become a model for studying multi-stage carcinogenesis. Four distinct sequential mutations have been described in the development of colon cancer. These are mutations of the APC (adenomatous polyposis coli), K-ras, DCC (deleted in colon cancer), and p53 genes. With each mutation, progressive changes are seen in the colonic epithelium (the cells on the internal surface of the colon).

Mutation of APC typically occurs early and is sometimes inherited. Mutations in APC lead to dysplasia (abnormalities in adult cells) or polyp formation (usually benign growths on the surface of mucous membranes). These polyps can remain dormant for many decades. When one cell in this polyp develops a second mutation, in the K-ras gene, it grows at a faster rate resulting in a larger tumor or intermediate adenoma. Subsequent mutations in DCC and p53 lead to late adenoma and finally carcinoma.

These mutations result in both the overexpression of oncogenes and the deletion of anti-oncogenes, the combination of which results in cancer. This is, however, just a model and not all genes are altered in all cases of colon cancer; additional mutations are likely. Individuals with the hereditary predisposition to colon cancer known as familial adenomatous polyposis (FAP) typically have inherited mutations of the APC gene, the first step of colon cancer. Only 15% of colon cancer cases are due to hereditary factors, however, with 85% due to sporadic mutations.

Resources

BOOKS

Kinzler, Kenneth W., and Bert Vogelstein. "Colorectal Tumors."In The Genetic Basis of Human Cancer. Volgelstein, B., and K. Kinzler, eds. New York: McGraw-Hill, 1998.

McKinnell, Robert G., Ralph E. Parchment, Alan O. Perantoni, and G. Barry Pierce. The Biological Basis of Cancer. New York: Cambridge University Press, 1998.

Templeton, Dennis J., and Robert A. Weinberg. "Principles of Cancer Biology" In Clinical Oncology. Murphy, G., W. Lawrence, and R. Lenhard, eds. Atlanta: The American Cancer Society, 1995.

Weinberg, Robert A. One Renegade Cell: How Cancer Begins. New York: Basic Books, 1998.

PERIODICALS

Weinstein, I. Bernard. "Disorders in Cell Circuitry During Multistage Carcinogenesis: The Role of Homeostasis." Carcinogenesis 21 (2000): 857-64.

OTHER

Mellors, Robert C. "Etiology of Cancer: Carcinogenesis." Neoplasia Weill Medical College of Cornell University. July 1999. 27 June 2001 <http://edcenter.med.cornell.edu/CUMC_PathNotes/Neoplasia/Neoplasia_04.html>.

Cindy L. A. Jones, Ph.D.