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Lynch Syndrome

NORD is very grateful to 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.

Synonyms of Lynch Syndrome

  • hereditary non-polyposis colon cancer
  • HNPCC
  • Muir-Torre syndrome
  • Turcot syndrome

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Lynch syndrome is an autosomal dominant cancer predisposition syndrome characterized by an increased risk for colon cancer and cancer of the stomach, small intestine, upper urinary tract, liver, brain and skin. Women with this condition also have an increased risk for cancer of the lining of uterus (endometrium) and ovaries.

Symptoms

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.

Causes

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.

Affected Populations

Lynch syndrome is the underlying cause of about 5% of all cases of colorectal cancer. The estimated prevalence of HNPCC is approximately 1/200-1/2,000.

Related Disorders

Symptoms of the following disorders can be similar to those of Lynch syndrome. Comparisons may be useful for a differential diagnosis.

Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps). If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum. FAP is inherited in an autosomal dominant manner and caused by abnormalities (mutations) in the APC gene. Mutations in the APC gene cause a group of polyposis conditions that have overlapping features: familial adenomatous polyposis, Gardner syndrome, Turcot syndrome and attenuated FAP. (For more information about this disorder, choose "polyposis" as your search term in the Rare Disease Database.)

Crohn's disease is an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or any portion of the gastrointestinal tract. The lower portion of the small intestine (ileum) and the rectum are most commonly affected by this disorder. Symptoms may include watery diarrhea, abdominal pain, fever, and weight loss. The symptoms of Crohn's disease can be difficult to manage and proper diagnosis is often delayed. The exact cause of Crohn's disease is unknown. (For more information about this disorder, choose "Crohn" as your search term in the Rare Disease Database.)

Peutz Jeghers syndrome (PJS) is an autosomal dominant genetic condition characterized by multiple benign polyps called hamartomas on the mucous lining in the gastrointestinal system. These polyps occur most often in the small intestine but also occur in the stomach and large intestine. Affected individuals also have dark skin discoloration, especially around the eyes, nostrils, mucous membranes of the mouth, perianal area and inside the mouth. Affected individuals have an increased risk for intestinal and other cancers. (For more information about this disorder, choose "Peutz-Jeghers" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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.

Treatment
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 10 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.

Investigational Therapies

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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Lynch Syndrome

References

JOURNAL ARTICLES
Burn, J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378(9809):2081-7.

Hampel H, Stephens JA, Pukkala E, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005;129:415-21.

Mueller-Koch Y, Vogelsang H, Kopp R, et al. Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut. 2005;54:1733-40.

Lipton LR, Johnson V, Cummings C,et al. Refining the Amsterdam Criteria and Bethesda Guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic. J Clin Oncol. 2004;22:4934-43.

Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-8.

Lucci-Cordisco E, Zito I, Gensini F, Genuardi M. Hereditary nonpolyposis colorectal cancer and related conditions. Am J Med Genet A. 2003;122:325-34.

Gruber SB, Kohlmann W. The genetics of hereditary non-polyposis colorectal cancer. J Nat Comp Cancer Net. 2003;1:137-44.

Brown GJ, St John DJ, Macrae FA, Aittomaki K. Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance. Gynecol Oncol. 2001;80:346-9.

Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116:1453-6.

Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248-57.

Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA. 1997;277:915-9.

Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst. 1997;89:1758-62.

Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 1995; 64: 430-3.

INTERNET
Kohlmann W, Gruber SB. (Updated August 11, 2011). Lynch Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 13, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/03/20 00:00:00 GMT+0

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