Molecular Medicine : Colon Cancer and DNA Repair

The Disease

Cancers of the colon and rectum (colo-rectal cancers) are one of the most common types of cancer in Western countries, accounting for nearly 140,000 cancer cases per year in the United States (approximately 10% of the total cancer incidence). Most colon cancers (like other types of cancer) are not inherited diseases; that is, they are not transmitted directly from parent to offspring. However, two inherited forms of colon cancer have been described. In both of these syndromes, the inheritance of a cancer susceptibility gene results in a very high likelihood of cancer development. One inherited form of colon cancer (familial adenomatous polyp-osis) is extremely rare, accounting for less than 1% of total colon cancer incidence. The second inherited form of colon cancer (hereditary nonpolyposis colorectal cancer, or HNPCC) is much more common and accounts for up to 15% of all colon cancer cases. Indeed, HNPCC is one of the most common inherited diseases, affecting as many as one in 200 people. Although colon cancers are the most common manifestation of this disease, affected individuals also suffer an increased incidence of other types of cancer, including cancers of the ovary and endometrium.

Molecular and Cellular Basis

Like other cancers, colorectal cancer results from mutations in genes that regulate cell proliferation, leading to the uncontrolled growth of cancer cells. In most cases these mutations occur sporadically in somatic cells. In hereditary cancers, however, inherited germ-line mutations predispose the individual to cancer development.

A striking advance was made in 1993 with the discovery that a gene responsible for approximately 50% of HNPCC cases encodes an enzyme involved in mismatch repair of DNA; this gene is a human homolog of the E. coli MutS gene. Subsequent studies have shown that three other genes, responsible for most remaining cases of HNPCC, are homologs of MutL and thus are also involved in the mismatch repair pathway. Defects in these genes appear to result in a high frequency of mutations in other cell genes, with a correspondingly high likelihood that some of these mutations will eventually lead to the development of cancer by affecting genes that regulate cell proliferation.

Prevention and Treatment

As with other inherited diseases, identification of the genes responsible for HNPCC allows individuals at risk for this inherited cancer to be identified by genetic testing. Moreover, prenatal genetic diagnosis may be of great importance to carriers of HNPCC mutations who are planning a family. However, the potential benefits of detecting these mutations are not limited to preventing the transmission of mutant genes to the next generation; their detection may also help prevent the development of cancer in affected individuals.

In terms of disease prevention, a key characteristic of colon cancer is that it develops gradually over several years. Early diagnosis of the disease substantially improves the chances for patient survival. The initial stage of colon cancer development is the outgrowth of small benign polyps, which eventually become malignant and invade the surrounding connective tissue. Prior to the development of malignancy, however, polyps can be easily removed surgically, effectively preventing the outgrowth of a malignant tumor. Polyps and early stages of colon cancer can be detected by examination of the colon with a thin lighted tube (colonoscopy), so frequent colonoscopy of HNPCC patients may allow polyps to be removed before cancer develops. In addition, several drugs are being tested as potential inhibitors of colon cancer development, and these drugs may be of significant benefit to HNPCC patients. By allowing the timely application of such preventive measures, the identification of mutations responsible for HNPCC may make a significant contribution to disease prevention.

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From: DNA Repair

Cover of The Cell
The Cell: A Molecular Approach. 2nd edition.
Cooper GM.
Sunderland (MA): Sinauer Associates; 2000.
Copyright © 2000, Geoffrey M Cooper.

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