Medical Author: Dennis Lee, MD
Medical Editor: Jay W. Marks, MD, and Barbara K. Hecht, Ph.D.

• Introduction
• What causes colon cancer?
• How does one acquire the mutations that cause colon cancer?
• What are hereditary colon cancer syndromes?
• Who should consider genetic counseling and testing?
• Why is genetic counseling and testing important in hereditary colon cancer syndromes?
• How is genetic testing conducted?

Introduction

Colon cancer is the fourth most common cancer in the United States. In the US an estimated 130,000 men and women will develop colon cancer and more than 50,000 will die from it each year. The life-time risk for individuals to develop colon cancer is approximately 6%, but the risk increases to 18% among individuals who have a first degree relative (parent, sibling or child) with colon cancer.

What causes colon cancer?

Mutant genes cause colon cancer. The human body is composed of trillions of cells. Inside each cell are two sets of 23 chromosomes, one set from each parent. Each chromosome contains long strands of DNA. The DNA encodes thousands of genes. The genes carry the genetic information that is passed down from both parents. Different genes are responsible for different structures and functions in the body. For example, some genes influence eye color, hair color, height, and other physical characteristics. Other genes regulate cell growth and division. Still other genes prevent cells from invading neighboring tissues or spreading to distant organs.

When genes that normally control cell multiplication and growth mutate (change), the cells may multiply and grow without restraint. When cells grow without restraint inside the colon, a colon polyp develops. If additional genetic changes occur in that polyp, the polyp can turn cancerous and invade adjacent tissue and spread to distant sites. The sequence of events by which polyps form, become cancerous, invade nearby tissue and spread can and often does take years.

How does one acquire the mutations that cause colon cancer?

Mutations (changes within individual genes) can be inherited from either or both parents or can be acquired any time after conception. Environmental factors such as radiation, chemicals, oxidants, and viruses may trigger these types of mutations.

Inherited mutations will end up in every cell in the body, whereas acquired mutations will be present only in the original cell in which it occurred and in all the cells descended from that original cell. For example, the mutation may be restricted to the cells of the polyp or cancer.

Generally, acquired mutations tend to cause only one or a few colon polyps that can be removed by colonoscopy. (For further information, please see the article on colonoscopy.) Removing these polyps effectively prevents the progression from colon polyp to colon cancer.

On the other hand, inherited gene mutations present in every cell have a tendency to cause numerous (sometimes thousands) of colon polyps. These polyps may be too numerous or too large to be removed by colonoscopy. In addition, the progression from polyp to invasive cancer may be so rapid that even frequent colonoscopy is not adequate to remove the polyps and prevent colon cancer.

Finally, some cancers may develop directly from cells of the colon lining, without the development of polyps that can be recognized and removed. For this reason, surgical removal of the colon may be necessary to prevent colon cancer in patients with inherited forms of colon cancer.

What are hereditary colon cancer syndromes?

Hereditary colon cancer syndromes are caused by specific inherited mutations that are sufficient in themselves to cause colon polyps, colon cancers, and non-colonic cancers. Hereditary colon cancer syndrome can affect multiple members of a family. Approximately 5% of all colon cancers in the US are due to hereditary colon cancer syndromes. Patients who have inherited one of these syndromes have an extremely high risk for developing colon cancer, approaching 90%-100%. Fortunately, blood tests are now available to test for these hereditary colon cancer syndromes, once a syndrome has been suspected within a family.

Familial adenomatous polyposis (FAP)

Familial adenomatous polyposis, or FAP is a hereditary colon cancer syndrome in which the affected family members develop large numbers (hundreds, sometimes thousands) of colon polyps starting in their teens. Unless the condition is detected and treated early (treatment involves removal of the colon), a family member with the FAP syndrome is almost sure to develop colon cancer. Cancers most commonly begin to appear when patients are in their 40's, but can appear earlier. These patients also are at risk of developing other cancers such as cancers of the thyroid gland, stomach, and the ampulla (the part of the duodenum into which the bile ducts drain).

Attenuated familial adenomatous polyposis (AFAP)

Attenuated familial adenomatous polyposis, or AFAP is a milder version of FAP. Affected patients develop less than 100 colon polyps. Nevertheless, they are at high risk of developing colon cancers at a young age. They are also at risk for stomach and duodenal polyps.

Hereditary nonpolyposis colon cancer (HNPCC)

Hereditary nonpolyposis colon cancer, or HNPCC, is a hereditary cancer syndrome in which affected family members tend to develop colon cancers, usually in the right colon, in their 30's to 40's. Certain HNPCC patients also are at elevated risk for developing uterine cancer, stomach cancer, ovarian cancer, cancers of the ureters (the tubes that connect the kidneys to the bladder), cancers of the bile ducts (the ducts that drain bile from the liver to the intestines), and cancer of the brain and skin.

Quick GuideColon Cancer: Symptoms, Signs, Screening, Stages

MYH polyposis syndrome

The MYH polyposis syndrome is a recently discovered hereditary colon cancer syndrome. Affected patients typically develop 10-100 polyps during their 40's and are at high risk for developing colon cancer. The MYH syndrome is inherited in an autosomal recessive manner with each parent contributing one copy of the mutant gene. Most people with the MYH syndrome do not have a multigenerational family history of polyps or cancer of the colon but may have brothers or sisters with it.

Who should consider genetic counseling and testing?

Genetic counseling followed by genetic testing should be considered for individuals as well as their family members when there are:

• Individuals in the family with early onset of colon cancer, before age 50
• Individuals in the family with numerous colon polyps
• Families in which multiple members have colon cancer
• Families with members with numerous colon polyps
• Families with members having colon cancers at young ages
• Families with members having certain non-colon cancers such as cancers of the uterus, thyroid, ureters, ovaries, small intestine, etc.

Genetic testing without prior counseling is discouraged because of the extensive family education that is involved and the complicated nature of interpreting the test results.

Why is genetic counseling and testing important in hereditary colon cancer syndromes?

Patients who have hereditary colon cancer syndromes usually have no symptoms and are unaware that they have colon polyps or early colon cancers. They usually will develop colon cancers early in life (often before ages 40-50). Therefore, to prevent colon cancers in patients with hereditary colon cancer syndromes, colon screening must begin early. For example, patients with FAP should have annual flexible sigmoidoscopies starting at age 12, patients with AFAP should have annual colonoscopies starting at age 25, and patients with HNPCC should have colonoscopies beginning at age 25 (or 10 years younger than the earliest colon cancer diagnosed in the family, whichever is earlier). The current screening recommendations for the general population (fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy beginning at ages 40-50) are inadequate for most patients with hereditary colon cancer syndromes.

Genetic counseling and testing are important to identify patients and family members with hereditary colon cancer syndromes so that screening with flexible sigmoidoscopies and colonoscopies can begin early and, if necessary, the colon can be removed surgically to prevent colon cancer. Moreover, depending on which hereditary colon cancer syndrome is present, early screening for other types of cancer such as ovarian, uterine, stomach, ureter, and thyroid may be appropriate.

How is genetic testing conducted?

Genetic testing should be done following genetic counseling, so that family members understand fully the advantages and limitations of genetic testing as well as how the tests should be interpreted.

Within the family, the first person to undergo genetic testing usually is the person who clearly has the disease (e.g., with numerous colon polyps with or without colon cancer). If genetic testing of this family member reveals a mutation responsible for a hereditary colon cancer syndrome, then other family members can be tested for the same mutation. Those family members who do not carry the mutation can be assured that they have not inherited the syndrome, whereas those who have the mutation should begin early screening for colon and other cancers. Depending on which syndrome is present and the age of the patient, removal of the colon may be recommended.

Unfortunately, genetic testing that shows no known cancer syndrome does not necessarily mean that there is no cancer syndrome. Our current knowledge about colon cancer syndromes is imperfect and our ability to recognize them is incomplete, and there may be unrecognized syndromes that cannot yet be detected. Even if no cancer syndrome is identified by genetic testing, first-degree relatives of someone with colon cancer are still considered at increased risk for developing colon cancer themselves and should undergo early screening as directed by their physicians.