NORD gratefully acknowledges Albert de la Chapelle, MD, PhD, Distinguished University Professor, Department of Molecular Virology, Immunology, and Medical Genetics, and Heather Hampel, MS, CGC, Clinical Associate Professor, Genetic Counselor, Department of Internal Medicine, at the Ohio State University Comprehensive Cancer Center, for assistance in the preparation of this report.
Individuals with Lynch syndrome usually develop colon polyps or cancer in the right side of the colon at an early age, with a mean age of onset of 44 years. The mean age of onset for endometrial cancer is 46 years and many women with Lynch syndrome, endometrial cancer occurs before colon cancer. The mean age of onset for stomach cancer is 56 years, and the mean age onset for ovarian cancer in Lynch syndrome is 42.5 years.
Abnormalities (mutations) in four mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) and the EPCAM gene cause Lynch syndrome. These types of gene mutations prevent the proper repair of DNA prior to cell division, allowing abnormal cells to divide and increasing the risk for cancer. Not all individuals with a mutation in a mismatch repair gene will develop cancer but the risk is significantly higher than for someone without one of these gene mutations. This is called a genetic predisposition.
The genetic predisposition to Lynch syndrome is inherited as an autosomal dominant genetic trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Most individuals with Lynch syndrome inherit the condition from a parent. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Lynch syndrome is the underlying cause of about 5% of all cases of colorectal cancer. The estimated prevalence of Lynch syndrome is approximately 1/400 which means this is one of the most common adult-onset disorders.
The testing strategy for an individual patient suspected to have Lynch syndrome will vary depending on family history and clinical criteria. The Amsterdam Criteria, modified in 1999, define the family history risk factors for Lynch syndrome. The modified Amsterdam Criteria are: Three or more relatives with colorectal cancer, one of whom is a first degree relative (parent, child, sibling) of the other two; two successive generations with an affected relative; one case of colorectal cancer occurring in a relative under age 50. Individuals who meet the Amsterdam Criteria are said to have hereditary non-polyposis colon cancer.
Family history alone cannot differentiate Lynch syndrome from other causes of colon cancer. Microsatellite instability testing (MSI) on colon tissue can help to determine if molecular genetic testing for the gene mutations associated with Lynch syndrome is indicated. MSI testing identifies stretches of DNA with a repetitive sequence (microsatellites) that are less likely to be repaired if a mutation in a mismatch repair gene is present which can lead to a different number of repeats in the microsatellite from a person’s tumor than the number of repeats found in the same microsatellite in the person’s blood. The Updated Bethesda Guidelines (2004) are the criteria used to help identify individuals that are appropriate for MSI testing.
Immunohistochemical (IHC) analysis on colon tissue is also used to identify individuals who might have Lynch syndrome. IHC analysis detects the proteins produced if the mismatch repair genes are normal. When a particular protein is not present, the gene responsible for production of that protein can assumed to have a mutation (either an inherited mutation in the case of Lynch syndrome or an acquired mutation such as hypermethylation of the MLH1 gene promoter which is not typically inherited).
Molecular genetic testing for mutations in the mismatch repair genes associated with Lynch syndrome is available to confirm the diagnosis. With the advent of next-generation sequencing panels, it is now possible to test individuals for all of the known Lynch syndrome genes at one time for minimal cost. As a result, an individual can be evaluated for Lynch syndrome by mutation testing of the Lynch syndrome genes with or without first performing tumor screening at this time.
Surgery is recommended to remove the colon (subtotal colectomy) if colon cancer is detected in someone with a known diagnosis of Lynch syndrome due to the high risk for second primary colon cancers. Surgery to remove the uterus and ovaries before cancer develops (prophylactic) is a consideration for women who have Lynch syndrome and have completed childbearing. Individuals with Lynch syndrome should be monitored every one or two years with examinations of the colon (colonoscopy) beginning at age 20-25 or 2 to 5 years before the youngest age that a family member was diagnosed, whichever is earlier. Prophylactic removal of the colon is not usually recommended because colonoscopy is usually effective in detecting colon cancer at an early stage or at preventing colon cancer entirely.
Genetic counseling is recommended for affected individuals and their family members. Other treatment is symptomatic and supportive.
Studies are ongoing to determine if COX-2 inhibitors can reduce the development of polyps in individuals with Lynch syndrome. There is now data that the daily use of 600 mg of aspirin for at least 2 years appears to decrease the risk for colon cancer among individuals with Lynch syndrome by 60% 3-5 years after they begin aspirin therapy. However, the optimal dose and duration of aspirin therapy is not yet known.
The effectiveness of oral contraceptives in reducing the risk for endometrial and ovarian cancer in women with Lynch syndrome is currently being studied.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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