Genetics of Colorectal Cancer

By Wylie Burke, MD, PhD

Colorectal cancer (CRC) has long been known to cluster in some families. Research on the genetics of colorectal cancer (CRC) now provides a guide to the inheritance of CRC risk. An important benefit of this research is the development of strategies to identify people with a genetic susceptibility to CRC so that targeted prevention can be offered. In the long term, this research will lead to a better understanding of the biology of CRC and may ultimately lead to new treatment and prevention strategies.

Family history as a risk factor for colorectal cancer
People who have a positive family history of CRC — that is, a history of close relatives with colon or rectal cancer — have an increased risk of developing this cancer themselves. The closer the relative, the greater the risk; therefore, risk is higher if a first-degree relative (a parent, brother or sister, or child) had CRC than if a second-degree relative (grandparent, aunt or uncle) did. Risk is also higher when relatives have been affected with CRC at a young age, particularly if cancer has occurred before age 50.

Most people with a family history of CRC have only one affected relative. About 5-10% of people fall into this category. However, a small proportion of people with a positive family history — less than 1% of the general population — are from high-risk families, characterized by multiple affected relatives and early onset of CRC. Two genetic conditions have been identified as the cause of these high-risk families: familial polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) (See Figure 1). Both of these conditions are rare, but people with these conditions require special approaches to early detection and treatment to reduce their cancer risk.

When a family history indicates the possibility of a high-risk family, further investigation is merited to determine whether these conditions are present. Specific family history characteristics that suggest an inherited cancer syndrome include colorectal cancer in succeeding generations, onset of cancer before age 50, and the presence of other cancers associated with an inherited risk of colorectal cancer, especially endometrial cancer. Suspicion increases with an increasing number of affected family members.

Using family history to make screening decisions
CRC screening is recommended for all Americans starting at age 50. Earlier initiation of testing — at age 40 — is recommended for people who have a first degree relative with CRC. If FAP or HNPCC is present, more aggressive approaches for early detection are needed to reduce colorectal cancer risk (See Figure 1). In the case of HNPCC, early detection testing for other cancers may be indicated as well. Most experts recommend endometrial cancer screening for women with HNPCC. Ovarian cancer and ureteral tract cancers may also occur in HNPCC families. Although early detection strategies are limited for these cancers, some experts recommend the use of screening measures such as serum CA-125 levels, pelvic ultrasound and urine cytology when these cancers are present in the family.

Family history evaluation is thus a two-step process. In the first step, the presence or absence of a family history of colorectal cancer is determined. If a positive history of CRC is found, the second step determines whether the family history indicates a possible high-risk family. An example of this approach to family history is outlined in the table here.

Some families fall into an intermediate category of risk. For example, a family may include two affected relatives, neither of whom was affected before age 50 or a single affected relative affected before age 40. In some cases, additional cancers may occur and confirm the family as high-risk. In other cases, the family remains in an intermediate category. A common approach to screening in such families is to initiate colorectal cancer screening ten years earlier than the age of diagnosis of the youngest affected family member. In addition, a personal or family history of colorectal cancer has been shown in epidemiological studies to be associated with a small increased risk for other common cancers such as breast cancer. Careful adherence to all routine cancer screening measures is recommended.

An unexpected negative effect of prevention:
The loss of evidence of a family history of CRC
The purpose of CRC screening is to find adenomatous polyps, which are pre-cancerous growths in the colon and rectum. When these are removed, CRC can be prevented. As a result, a person who might otherwise have developed CRC has, instead, a medical history of an adenomatous polyp. Because this medical history is not as dramatic as a history of cancer, people may not discuss their polyps with family members. However, a family history of adenomatous polyps is also a risk factor of colorectal cancer. If multiple family members have had adenomatous polyps removed, this family history could be an indicator of a high-risk family, even if no colorectal cancer has occurred. This is particularly the case if the polyps were removed at a young age (for example, before age 50). New efforts are needed to help doctors and patients to communicate to family members the importance of a family history of adenomatous polyps.

Genetic Testing
Genetic testing may have value in high-risk families. Genetic testing refers to a blood test to evaluate for the presence of a mutation on one of the genes known to cause inherited risk of CRC. Genetic testing is not a foolproof way to determine risk: even when the family history indicates a high-risk, testing may not identify a mutation. For example, genetic testing will identify a mutation in most but not all families with FAP, and will identify a mutation in only 60-70% of families with HNPCC (See Figure 1). These numbers indicate that additional mutations causing inherited risk of CRC are yet to be found.

Figure 1

In addition to mutation tests for FAP and HNPCC, a genetic test has recently been developed for a genetic variant called APC I1307K. This variant is found in about 6% of people of Jewish descent. Several studies suggest that this gene variant causes an approximately two-fold increased risk of colorectal cancer. The clinical value of testing for the I1307K variant is uncertain. It is not yet known whether the variant leads to earlier onset of cancer or more rapid progression of polyps to cancer. As a result, it is not yet clear whether the I1307K carrier state should guide decisions about the age at which colorectal cancer screening is initiated, or the optimal screening strategy.

Genetic testing offers the opportunity to identify those individuals within a high-risk family who have inherited the cancer predisposition. This risk information may be helpful in planning decisions about cancer surveillance or use of prophylactic surgery. Some people may want to use it in making family planning or career decisions.

Because a mutation will not always be found, the optimal testing strategy is to test one or more affected relatives first. Then, if a mutation is identified, testing can be offered to unaffected individuals, to determine whether or not they have inherited the cancer predisposition. However, if a mutation cannot be identified in an affected family member, further testing will be non-informative and should not be pursued.

Genetic testing involves potential risks as well as benefits. Experts agree that individuals contemplating testing should have the opportunity to consider these issues carefully prior to deciding whether or not to be tested. Risks of a positive genetic test include anxiety and family distress, and the potential for stigmatization and loss of insurance or employment opportunities. Typically, family members are offered pre-test counseling to consider these issues before proceeding, and are offered post-test counseling to review all the implications of the test results.

Editors’ note: Dr. Burke is a member of the CCA Science Advisory Board and is an Internist and Geneticist at the University of Washington.

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