Familial Colorectal Cancers: Hereditary Non-Polyposis Colon Cancer (HNPCC)
Hereditary Non-Polyposis Colon Cancer
Colorectal cancers are some of the most common cancers in industrialized countries. In 2001, there were an estimated 135,400 new cases and 56,700 deaths in the United States. Approximately 10 to 15% of cases may be caused by genetic abnormalities that run in families. There are two major types of hereditary disorders that lead to colorectal cancers, familial adenomatous polyposis (also known as FAP) and hereditary non-polyposis colorectal cancer (HNPCC). HNPCC accounts for about 5 to 10% of all colorectal cancers, while FAP cases make up only about 1%. In this issue of eNews, we will discuss HNPCC; FAP will be discussed in a future issue.
Dr. Henry Lynch first described HNPCC and the disorder is often referred to as Lynch Syndrome. He further specified that families either had Lynch type I (also called HNPCC type A) or Lynch type II (also called HNPCC type B). Families with Lynch type I often report numerous cases of colorectal cancers in young (under age 50) relatives. The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome (which is often referred to as a sporadic cancer). Families with the Lynch II syndrome will also report colorectal cancers in young relatives, but will also have cases of "HNPCC related cancers". These related cancers include breast, endometrial, gastric, ovarian, and ureter.
Although many patients may have similar family histories, specific criteria must be met and certain genetic abnormalities must be present for a family to be classified as HNPCC. The genes that have been identified as responsible for HNPCC are MSH1, MSH2, PMS1, and PMS2. Individuals with a mutation in any one of these genes have an estimated 80% lifetime risk of developing colon cancer. People with HNPCC are most likely to develop cancer on the right side of the colon, unlike most sporadic cases, which develop on the left side of the colon. Flexible sigmoidoscopy, a standard screening test for colorectal cancer, only examines the left side of the colon, and is a poor screening test for this population. While people with HNPCC develop polyps at the same rate as other people, these polyps are more likely to progress to cancer. In addition, the progression of polyps to cancer occurs in a shorter period of time compared to sporadic cases on colorectal cancer.
In order to better define families with HNPCC, a panel of experts met in 1990 in Amsterdam to develop criteria for the syndrome, often referred to as the Amsterdam criteria. In the years following this meeting, genetic testing became more readily available and a number of families have been found to carry one of the genetic abnormalities, but do not fit the original criteria. For this reason, in 1999, the Amsterdam criteria II were developed, and now serve as the necessary criteria for HNPCC families.
The criteria are:
- There should be at least 3 relatives with a HNPCC associated cancer (colorectal, endometrial, small bowel, ureter, or ovarian).
- One should be a first degree relative of the other two (a first degree relative is a parent, sibling, or child).
- At least 2 successive generations should be affected.
- At least 1 should be diagnosed before age 50.
- FAP must be ruled out, and the tumors must be verified by pathology.
Families with histories meeting the criteria may wish to undergo genetic testing to determine if they carry the defective gene. If this test is positive (usually done on the affected family member's tumor) for a genetic abnormality, other family members at risk can then be tested for the same abnormality. If no abnormality is detected in the family member's tumor, then testing other family members would not be informative. However, the tests that are currently available are not 100% accurate. Depending on the methods used, they can miss positive cases anywhere from 5 to 50% of the time. A family may carry a mutation in a gene that has not yet been discovered or a mutation for which that testing has not yet been developed.
Genetic testing is something that should not be taken lightly. One must consider the effect of the outcome of the test not only on themselves, but also in other family members. Concerns may include the availability, or lack of preventive options, passing the gene on to one's children, and discrimination in employment and insurance matters. To assist in this difficult decision, a genetic counselor should meet with anyone wishing to undergo testing. These professionals are trained to help patients understand the issues surrounding genetic testing, and help them make the right decision for them and their family.
People with HNPCC tend to develop cancers earlier than the general population, and therefore should begin screening earlier. It is estimated that 15% of people with HNPCC will develop colorectal cancer by age 40. People with HNPCC should have a colonoscopy beginning at age 20 to 25 years, and repeated every 1 to 2 years. Women in these families are at increased risk for endometrial cancer, and should consider annual transvaginal ultrasound or endometrial biopsy starting at age 25 to 35.
Scientists have learned a great deal about genetic syndromes in the past 10 years. This is, in part, due to the involvement of patients in research studies. If you have a family history of cancer and would like to learn more about cancer risk and research, check out the links below.
American Cancer Society, 2001 Statistics.
CancerNet, A service of the National Cancer Institute. Genetics, Causes, Risk Factors, Prevention of Colon and Rectal Cancer.
Lenhard, R. E., Osteen, R. T., & Gansler, T. (Eds.): The American Cancer Society's Clinical Oncology (2001). The American Cancer Society, Atlanta, Georgia.
Vasen HF, Watson P, Mecklin JP, et al.: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116(6): 1453-1456, 1999.
Yarbro, C. H., Frogge, M. H., Goodman, M., & Groenwald, S. L. (Eds.): Cancer Nursing: Principles and Practice (2001). Jones and Bartlett Publishers, Boston, Massachusetts.