Familial Colorectal Cancers: Hereditary Non-Polyposis Colon Cancer (HNPCC)
Colorectal cancer is the fourth most commonly diagnosed cancer in the United States. There will be an estimated 150,000 cases diagnosed annually in the US. Approximately 10 to 15% of these cancers may be caused by genetic abnormalities that run in families. There are two major types of known hereditary disorders, familial adenomatous polyposis (also known as FAP) and hereditary nonpolyposis colorectal cancer (also known as Lynch Syndrome and HPNCC). In this article, we will address HNPCC. HPNCC is the most common type of hereditary colorectal cancer, responsible for an estimated 3-5% of all colorectal cancer diagnoses.
Dr. Henry Lynch first described HPNCC in 1966, when it was 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 colon cancer in patients with this syndrome is 44 years old, as compared to 68 (for men) and 72 (for women) years old in people without a genetic syndrome (which is often referred to as a sporadic cancer).
Families with Lynch Type II syndrome will also report colorectal cancers in young relatives, and in addition, have cases of "HNPCC related cancers.” These related cancers include endometrial, gastric, ovarian, small intestine, liver/bile duct, brain, skin, and urinary tract.
Criteria for HNPCC
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 MLH1, MSH2, MSH6, PMS1, and EPCAM. Individuals with a mutation on 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 sporadic cases, which more often 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 of colorectal cancer.
The Amsterdam II criteria are useful in identifying families with an elevated risk of HPNCC. These criteria state that HPNCC should be suspected in families when:
- There are at least 3 relatives with HNPCC associated cancer (colorectal, endometrial, small bowel, ureter, or ovarian), one of whom is a first-degree relative (parent, sibling, or child) of the other two.
- At least 2 successive generations should be affected.
- At least 1 should be diagnosed with cancer before age 50.
- FAP (Familial adenomatous polyposis)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 for a genetic abnormality (test is usually done on the affected family member's tumor sample), other family members at risk can then be tested for the same abnormality and be given guidance regarding cancer screening.
If an abnormality is not detected in the family member's tumor, then testing other family members would not be informative. It is important to remember that a negative result is not always helpful. It just means the laboratory did not find a mutation in the genes they were examining. This could mean that there is no genetic mutation causing this cancer or increasing this family’s cancer risk. However, it could also mean that the test was not able to detect a mutation - even though one exists. This could happen if the family carries a mutation in a gene that has not yet been discovered or a mutation for which 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 on 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 decision, a genetic counselor should meet with anyone considering testing. These professionals are trained to help patients understand the issues surrounding genetic testing and results, and help them make the right decision for themselves and their family.
Cancer Screening in HNPCC
People with HNPCC tend to develop cancers earlier than the general population, and therefore should begin screening earlier. Several organizations have published guidelines on cancer screening for people with HNPCC mutations, including the American College of Gastroenterology, United States Multi-society Task Force on Colorectal Cancer, American Society of Clinical Oncology, and National Comprehensive Cancer Network. The following is a summary of the recommendations of these groups, but you should discuss your history and screening plan with your genetic counselor or physician.
- Undergo colorectal cancer screening with colonoscopy every 1-2 years beginning between ages 20 to 25 years or 2-5 years before the earliest age of colorectal cancer diagnosis age in the family – whichever comes first.
- Screening for gastric cancer can be done with upper endoscopy, starting between ages 30-35 years. If H. Pylori is found, it should be treated. The test should be repeated every 3 to 5 years.
- Have an annual skin exam to look for skin cancers associated with Lynch Syndrome.
- Mutation carriers who have had one or more first-degree relatives with pancreatic cancer may benefit from screening for pancreatic cancer.
- Women should have an annual pelvic exam and endometrial biopsy every 1-2 years, starting at age 30-35 or 3-5 years earlier than the earliest age of diagnosis of gynecologic cancer in the family.
- Some women may choose to have ovarian cancer screening with transvaginal ultrasound and CA-125 levels starting at age 30-35 or 5-10 years before the earliest age of diagnosis in the family. The benefit of this screening has not been proven.
Researchers have learned a great deal about genetic syndromes in the past 20 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.
Resources for More Information
For general Lynch Syndrome (HPNCC) information visit, Lynch Syndrome International.
Find a genetic counselor in your area.
Learn more about cancer family registries.
Learn more about screening through the Lynch Syndrome Screening Network.
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Kravochuck, S. E., Kalady, M. F., Burke, C. A., Heald, B., & Church, J. M. (2014). Defining HNPCC and Lynch syndrome: what's in a name? Gut, 63(9), 1525-1526.
Lynch, H. T., Snyder, C. L., Shaw, T. G., Heinen, C. D., & Hitchins, M. P. (2015). Milestones of Lynch syndrome: 1895-2015. Nature Reviews Cancer, 15(3), 181-194.
National Institute of Health (NIH): Genetics Home Reference. Lynch Syndrome. (2019). Retrieved from https://ghr.nlm.nih.gov/condition/lynch-syndrome#statistics
Provenzale D, Gupta S, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2019, National Comprehensive Cancer Network.
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SEER Statistics: Colon and Rectum Cancer. https://seer.cancer.gov/statfacts/html/colorect.html
Stoffel, E. M., Mangu, P. B., Gruber, S. B., Hamilton, S. R., Kalady, M. F., Lau, M. W. Y., ... & Limburg, P. J. (2015). Hereditary colorectal cancer syndromes: American society of clinical oncology clinical practice guideline endorsement of the familial risk–colorectal cancer: European society for medical oncology clinical practice guidelines. Journal of clinical oncology, 33(2), 209.
Syngal, S., Brand, R. E., Church, J. M., Giardiello, F. M., Hampel, H. L., & Burt, R. W. (2015). ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. The American journal of gastroenterology, 110(2), 223.