Lynch syndrome
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most prevalent form of hereditary colorectal cancer, accounting for about 5% of all colorectal cancer cases. Individuals with Lynch syndrome face a significantly increased risk of various cancers, including colorectal, stomach, small bowel, bladder, brain, and skin cancers, as well as endometrial and ovarian cancers in women. This genetic condition arises from mutations in mismatch repair (MMR) genes, which are crucial for repairing DNA errors. Diagnosis often involves assessing family history and confirming the presence of genetic alterations in MMR genes through testing.
Despite its name, individuals with Lynch syndrome can still develop polyps, but usually fewer than in other hereditary colorectal cancer forms. Regular screening, including colonoscopies starting at ages 20-25 or ten years before the earliest family diagnosis, is vital due to the aggressive nature of associated cancers. Treatment options for Lynch syndrome-related cancers typically include chemotherapy, radiation, and surgery, dependent on the cancer type. Preventative strategies, including the use of NSAIDs and regular screenings, can improve outcomes significantly, making early detection crucial for better survival rates among individuals with this syndrome.
Lynch syndrome
ALSO KNOWN AS: Lynch syndrome I; Lynch syndrome II; hereditary nonpolyposis colorectal cancer; HNPCC; familial nonpolyposis colon cancer; hereditary nonpolyposis colorectal neoplasm
DEFINITION Lynch syndrome (LS) is the most common form of hereditary colorectal cancer, causing an estimated 5 percent of all colorectal cancer cases. Confirming the diagnosis is of utmost importance because of the high lifetime risk for colorectal cancer and LS-associated cancers.
Risk Factors
Lynch syndrome poses an increased risk of colorectal, stomach, small bowel, gallbladder duct, upper urinary tract, brain, and skin cancers. Women with LS have additional risk of endometrial and ovarian cancer. A diagnosis can be made by family history and is typically confirmed with the finding of a genetic alteration (mutation) in a mismatch repair (MMR) gene.
Etiology and Genetics
Lynch syndrome is inherited in an autosomal dominant fashion, with most individuals inheriting this altered gene from their parent.
Lynch syndrome is most commonly associated with gene changes (mutations) found in mismatch repair genes. When functioning properly, MMR genes routinely repair damaged or erroneous sections of DNA (deoxyribonucleic acid). However, with only one functioning copy of the MMR gene, the cell is less able to repair the mistakes in DNA that accumulate. As abnormal cells continue to grow and divide, the mistakes are perpetuated, and can result in uncontrolled cell growth and possibly cancer.
Researchers best understand the significance of four MMR genes. Genetic variations in MMR genes named MLH1 (on chromosome 3), MSH2 and MSH6 (both on chromosome 2), and PMS2 (on chromosome 7) increase the risk of developing colorectal and LS-related cancers. Inactivation may result from deletions, mutations, or splicing errors occurring anywhere throughout the gene. The genes responsible for 20 to 25 percent of colorectal cancer cases are currently unknown and have not yet been discovered.
Having LS confers an increased risk of cancers. The lifetime risk of colorectal cancer for men with LS is from 60 to 80 percent; the figure is 40 to 60 percent for women. Women also have an increased risk of 40 to 60 percent for endometrial cancer throughout the lifetime.
Symptoms
Despite the term “nonpolyposis,” patients with hereditary nonpolyposis colorectal cancer (HNPCC), another name for LS, do have polyps. Individuals with HNPCC tend to develop less than one hundred polyps, which is much fewer than other forms of inherited colorectal cancers. Polyp formation generally begins with patients between twenty and thirty years of age. The polyps are typically right-sided adenomas that can be more aggressive than nonhereditary colorectal cancers.
Screening and Diagnosis
Individuals with a strong family history of cancer are encouraged to seek genetic counseling to determine their personal risk status. Carrier testing via DNA analysis (called microsatellite instability testing) may be useful to confirm or rule out personal risks. DNA testing is not usually recommended for individuals under the age of eighteen; however, screening for colorectal cancer may be initiated.
Individuals with colorectal cancer or other LS-associated cancers often confirm the diagnosis of LS by testing the tumor directly. Current practices include DNA testing MMR genes for instability (microsatellite instability, or MSI testing). The tumor can also be tested by chemically staining thin sections (immunohistochemistry), which are later evaluated by a pathologist.
Full colonoscopy screenings should be performed every one to two years because of the aggressive nature of LS-associated colorectal cancers. Colonoscopy screening should be initiated between the ages of twenty and twenty-five, or ten years before the earliest age of diagnosis in the family (whichever comes first).
Endometrial and ovarian cancer surveillance is less established than screening for colorectal cancer. In addition to annual examinations, annual transvaginal ultrasounds and the CA-125 blood test are also available.
Other screening practices are also available for stomach and urinary tract cancers, including gastroscopy and ultrasonography, respectively. No specific screening recommendations are currently available for gallbladder and brain cancers.
Treatment and Therapy
Treatment of colorectal cancers and other LS-associated cancers is dependent upon the nature of the cancer. Typically, chemotherapy, radiation therapy, and surgery are available as effective treatments.
Prevention and Outcomes
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin has been shown to be effective in preventing some colorectal cancers in patients with other types of hereditary colorectal cancer conditions. Research indicates it can be effective in patients with LS as well. Clinical trials are underway to explore whether a vaccine could help prevent colorectal cancer.
Oral contraceptives have been shown to reduce the risk of ovarian and endometrial cancers in the general public; however, it is not known whether they are as effective in risk reduction for individuals with LS.
Because routine colonoscopy is effective in detecting colon cancer, prophylactic surgery (removal of the colon) is generally not recommended for individuals with LS. Upon the finding of initial colorectal cancer, however, colectomies are recommended given the accelerated rate of carcinogenesis of LS-related colorectal cancers.
Prophylactic removal of the uterus and ovaries after childbearing years is optional for females with concerns with gynecologic cancers associated with LS.
In general, LS-associated cancers have the most positive outcome when detected early; thus adhering to recommended screening practices is essential to optimal care. Patients with Lynch syndrome have better rates of survival after colorectal cancer in comparison to patients with sporadic (nonhereditary) colorectal cancers.
Bibliography
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Lindor, N. M., et al. “Recommendations for the Care of Individuals with an Inherited Predisposition to Lynch Syndrome: A Systematic Review.” JAMA 296.12 (2006): 1507–517.
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Munoz, Juan Carlos. “Hereditary Colorectal Cancer.” Medscape. WebMD, 18 Apr. 2013. Web. 1 Aug. 2014.
Vilar-Sanchez, Eduardo. "Lynch Syndrome: 10 Things to Know About This Genetic Condition." MD Anderson Cancer Center, 24 Apr. 2024, www.mdanderson.org/cancerwise/qa-understanding-and-managing-lynch-syndrome.h00-158589789.html. Accessed 4 Sept. 2024.