Colon Cancer: Genetic Issues
by Beth A. Pletcher, MD, March 1998

In 1997 there were approximately 94,100 cases of colon cancer diagnosed in the United States and 46,600 deaths due to colon cancer. While the majority of cases of colon cancer occur in the absence of a strong family history and many are sporadic lesions, there are a growing number of genes that have been identified that increase ones risk of developing colon cancer.

The three genes that have been well characterized and are strongly associated with colon cancer are: FAP (familial adenomatous polyposis) and two genes associated with hereditary non-polyposis colorectal cancer (HNPCC) designated MSH2 and MLH1.

The FAP gene is best known because of the dramatic pathologic findings, well understood mode of inheritance (autosomal dominant) and complete penetrance we see in this small subset of families. The FAP gene known as APC has been localized to the long arm of chromosome 5 and mutations are generally associated with the progressive development of multiple colonic polyps, each one having the potential to undergo malignant transformation. For an individual who has inherited FAP, the lifetime risks for developing colon cancer are between 90 and 100%. However, this condition is treatable and even curable with screening colonoscopies and surgical resection. Genetic testing has become the standard of care for at-risk family members and can significantly improve the lives of non-carriers. A young person who is found not to carry the FAP gene can forego annual colonoscopies and surveillance generally recommended for individuals who were previously felt to be at high risk.

A single mutation in the APC gene has been identified in the Ashkenazi Jewish population and seems to carry with it a 20-30% lifetime risk for developing colorectal cancer. This point mutation is interestingly not associated with polyps and is found in approximately 6% of this population. Screening for this single mutation may be made available for Ashkenazi Jewish patients who have a family history of colon cancer.

The problem with HNPCC is that there are no polyps or other clues to suggest that an individual may be at high risk. In this case one needs to depend on a family history to assess risks and determine who may benefit from genetic screening. HNPCC has been associated with other tumor types in addition to colorectal cancer including endometrial and/or ovarian cancer in women. A set of criteria known as the Amsterdam Criteria have been developed to identify individuals at greatest risk for carrying a HNPCC gene. These criteria are: 1) at least three relatives with colon cancer 2) colon cancer in at least two generations 3) at least one person diagnosed with colon cancer before age 50 years.

Microsatellite testing can now be done for the HNPCC genes for patients at greatest risk. This testing is being offered to patients who meet the Amsterdam Criteria or fit into one of three other categories: 1) the patient has two HNPCC related cancers: endometrial, ovarian, gastric, hepatobiliary, small bowel or transitional cancer of the renal pelvis/ureter 2) the patient was diagnosed with colorectal or endometrial cancer before age 45 3) the patient was diagnosed with right-sided colorectal cancer.

For patients coming into your office today the risks for developing colon cancer are as follows:

1. general population lifetime risk = 3.5%

2. prior colorectal cancer successfully treated = 15%

3. first degree relative with colorectal cancer = 15%

4. colonic adenomas found on exam = 20%

5. Crohn's disease = 15-20%

6. Ulcerative colitis = 50-90%

7. carries a HNPCC gene = 50-70%

8. carries the FAP gene = 100%

If testing is indicated and patients feel they would like to be tested, it is important to keep in mind the fact that this information has serious implications for other family members such as siblings and children. How and when to tell family members is often a major issue and should be considered before proceeding with gene testing.