Colon Cancer

Colon cancer is the second leading cause of cancer death in the United States, occurring in approximately 5 percent of the population and resulting in roughly 55,000 deaths annually. New cases of colorectal cancer are diagnosed in approximately 90 per 100,000 people annually. The majority of cases occur in individuals older than age fifty. Of those who suffer from colorectal malignancy, an estimated 40 percent will die from the disease.

Colon cancer-related health-care costs, consisting of outpatient visits, hospitalizations, hospice and home health care, medications, and physician services, exceed $5 billion per year. This figure does not include the indirect costs of wages lost and reduced productivity.

Developing Cancer

The colon, also known as the large intestine, is the final portion of the digestive tract and consists of a tube (called the lumen) lined by specialized cells called colonic epithelial cells. These cells are constantly reproducing in a regulated manner, but when the growth and division of colonic epithelial cells becomes unregulated, colon cancer may result.

Cancer is a form of unregulated cell growth in which growing cells invade surrounding tissue. Such a growth is said to be malignant. Colon cancer results when there are certain changes in the genes that control normal cell replication. In most cases, when cell growth becomes abnormal, a visible growth (lesion) protrudes into the colon's lumen and is termed an adenomatous polyp (or adenoma). The polyp is not yet cancerous but may become so, at which point it is called carcinoma. This process, in which normal tissue becomes cancerous, is known as the adenoma-carcinoma sequence and may take between ten and fifteen years.

Major Genes Involved

The genes altered in the adenoma-carcinoma sequence normally play a role in regulating the cell cycle, controlling the division and turnover of epithelial cells. DNA mutations result in a loss of function of the gene and subsequent unregulated cell growth. While many genes have been studied, the ones most commonly associated with the majority of colon cancers are APC, p53 and K-ras.

Colorectal cancer may develop in an individual who has a strong inherited risk. This occurs, for example, in patients with familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC). These patients will usually have a specific genetic alteration.

APC.

The Adenomatous Polyposis Coli (APC) gene is found on chromosome 5 and is a tumor suppressor gene. Both alleles of the gene must be inactivated for tumor growth to occur. In the normal cell, the APC gene plays a role in regulating the cycle of cellular division and replication, as well as in cell-to-cell communication, thereby suppressing tumor development. Mutations of APC result in a loss of gene function, thus allowing unregulated cellular proliferation. APC mutations are found in the majority of common colon polyps and cancers and in patients with FAP, and they may be one of the earliest genetic alterations in the adenoma-carcinoma sequence.

K-ras.

The K-ras gene plays an active role in cellular signaling and promoting cell growth. The normal gene exists in both an active and inactive form. However, in the abnormal state, the active form predominates and results in a continually growth-stimulated state.

p53.

The normal p53 gene is responsible for regulating cells with damaged DNA by directing abnormal cells either to halt the cycle of cell division or to die as the result of a process called apoptosis. Like APC, the p53 gene is a tumor suppressor. With the p53 mutation, the gene no longer functions, and this permits the uninhibited proliferation of cells that may have damaged DNA. p53 mutations are seen in more than half of colorectal cancers.

Familial Adenomatous Polyposis (FAP)

FAP is characterized by the presence of hundreds or thousands of colonic polyps, and it accounts for less than 1 percent of colon cancers. Affected individuals are at increased risk of colorectal polyps and malignancy, and they usually develop polyps by age thirty-five and cancer by age forty. Because endoscopic removal of all the polyps is impossible, patients are usually advised to consider colectomy at a relatively young age. In addition to occurring in the colon, polyps occur in the upper digestive tract, and a variety of tumors may develop outside the gastrointestinal tract. Because mutations in the APC gene can be identified in most cases, genetic testing is now available for affected families.

FAP is inherited as an autosomal dominant disorder with 95 percent penetrance, meaning 95 percent of those who inherit one mutated APC gene will develop FAP. At the cellular level, the APC mutation is actually recessive: As long as there is one copy that is not mutated, the cell cycle will remain controlled.

The apparent paradox of a recessive gene causing a dominant disorder is resolved when we consider how a gene defect predisposes a person to cancer. Of the many millions of cells lining the colon, it is highly likely that some will undergo spontaneous mutation in one of the two copies of the APC gene.

For a person not affected by the APC gene, a spontaneous mutation of one allele will not lead to cancer, because the other gene copy remains intact. However, for a person affected who inherits one mutated copy of the APC gene, each of the cells lining the colon begins with one bad gene copy. Any mutation to the remaining good copy will cause the cell to lose control of its cell cycle and begin the process of polyp development. Given the number of cells involved, it is almost inevitable that this will occur in some of them. Hence FAP is a dominant condition.

Hereditary Nonpolyposis Colon Cancer

HNPCC is an autosomal dominant disorder that may be responsible for up to 5 percent of colon cancers. The genetic mutation leading to the abnormality is the mutation of DNA mismatch repair genes. Individuals with this mutation have up to an 80 percent chance of developing colon cancer. At least five genes are involved in this syndrome.

Malignancy in patients with HNPCC occurs at a younger age than in the general population, is more often located in the proximal colon (the portion nearest the small intestine), and may be associated with multiple tumors. HNPCC also carries an increased risk of tumors of the endometrium, ovaries, stomach, small intestine, bile ducts, bladder, renal pelvis, and ureters. Genetic testing is useful for HNPCC families.

Genetic Testing

Genetic testing may benefit patients and families affected by an inherited colon cancer syndrome. The genetic mutations in FAP and HNPCC can often be characterized. If a family member with colon cancer has an identified genetic abnormality, other family members can be tested to see if they have the same abnormality.

If the mutated gene is not found, the abnormal gene was not inherited and the family member is not at increased risk of developing cancer. Because screening (i.e., colon examination) is more frequently performed for those with FAP and HNPCC than others, genetic testing can be useful for determining who would benefit from intense surveillance.

Other Risk Factors

In addition to the well-described genetic syndromes of FAP and HNPCC, other factors that place an individual at increased risk include a personal or family history of colon cancer and the presence of inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease). Population studies support an association between the development of colon cancer and a high-fat, low-fiber diet, although a cause-and-effect relationship has not been proved.

Prevention

Inhibiting the development of polyps and cancers, finding and removing premalignant polyps, and testing individuals at high risk may reduce colon cancer-related morbidity and mortality. Colon cancer occurs less commonly in individuals whose diets are high in calcium and folate, who take multivitamins, and who maintain high-fiber and low-fat diets.

Non-steroidal anti-inflammatory medications like aspirin may reduce the numbers of polyps, particularly in families with FAP. Colonoscopy can identify polyps that may be premalignant and can facilitate polyp removal. It is recommended that all individuals have a colonoscopy at age fifty. Highrisk patients, such as those with inflammatory bowel disease, FAP, or HNPCC, should have screening initiated at an earlier age and repeat exams at shorter time intervals.

David E. Loren

and Michael L. Kochman

Bibliography

Giardiello, Francis M., Jill D. Brensinger, and Gloria M. Petersen. "AGA Technical Review on Hereditary Colorectal Cancer and Genetic Testing." Gastroenterology 121 (2001): 198-213.

Yamada, Tadataka, et al., eds. Textbook of Gastroenterology, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 1999.

Internet Resource

"The Burden of Gastrointestinal Diseases." American Gastrointestinal Association. May 2001. <http://www.gastro.org/pdf/burden-report.pdf>.