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Lynch syndrome (LS) is an adult-onset, cancer predisposition syndrome. It is caused by a mutation in one of the genes involved in the mismatch repair (MMR) pathway. Individuals with LS are at increased risk for colorectal and other cancers, includingendometrial, gastric, ovarian, pancreas, urothelial, brain (usually glioblastoma), biliary tract, small intestine, as well as sebaceous skin lesions and keratoacanthomas. Individuals with LS tend to have cancer at an earlier age than the general population and have higher risk for metachronous colorectal cancer and a second primary tumor in a different tissue. Lynch syndrome is not associated with any unique physician exam findings.
Cancer risks, through age 80, associated with Lynch syndrome mutations
| MLH1 | MSH2/EPCAM | MSH6 | PMS2 | General population |
Colorectal | 46-61% | 33-52% | 10-44% | 8.7-20% | 4.1% |
Endometrial | 34-54% | 21-57% | 16-49% | 13-26% | 3.1% |
Ovarian | 4-20% | 8-38% | Up to 13% | Up to 3% | 1.1% |
Gastric | 5-7% | 0.2-9% | Up to 8% | NE | 0.8% |
Pancreas | 6.2% | Not increased | Not increased | Not increased | 1.7% |
Bladder | 2-7% | 4.4-12.8% | Up to 8.2% | Not increased | 2.3% |
Biliary tract | 1.9-3.7% | Up to 1.7% | <1% | Up to 1% | 0.2% |
Renal pelvis and/or ureters | 0.2-5% | 2.2-28% | 0.7-5.5% | Up to 3.7% | <1% |
Small bowel | 0.4-11% | 1.1-10% | Up to 4% | Not increased | 0.3% |
Prostate | Up to 13.8% | Up to 23.8% | Not increased | Not increased | 12.6% |
Brain/CNS | 0.7-1.7% | 2.5-7.7% | 0.8-1.8% | Up to 1% | 0.5% |
NE: Not well-established
Adapted from: NCCN v.1.2023About 2-4% of colorectal cancers and 0.8-1.4% of endometrial cancers can be attributed to Lynch syndrome. An estimated 1 in 300 individuals in the general population have LS. Statistical algorithms are available to determine the likelihood of a Lynch-associated mutation based on personal and family history.
An individual should have a mutation identified through molecular testing of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or EPCAM gene.
LS is caused by a mutation in a mismatch repair (MMR) gene, which includesMLH1, MSH2, MSH6, and PMS2, or the EPCAM gene, which is involved in MMR gene expression. MMR is a DNA repair process in which the MMR proteins correct errors that occur during DNA replication.
LS is an autosomal dominant condition. First-degree relatives of a mutation carrier have a 50% chance of also carrying the mutation. Men and women are equally likely to inherit, and pass on, a mutation.
While rare, individuals with Lynch syndromemutations should be aware that if they have a child with another person who also has Lynch syndrome, the child has a 25% chance of carrying two mutations in the same gene, causing Constitutional Mismatch Repair Deficiency (CMMRD), characterized by brain, blood, gynecological, and certain pediatric cancers.
Clinical testing options include tumor analysis with immunohistochemistry (IHC) and/or microsatellite instability (MSI) and molecular analysis of theMLH1, MSH2, MSH6, PMS2, and EPCAM genes. In general, the recommended testing protocol for an individual with cancer is to begin with tumor screening using IHC and/or MSI, and proceed to multigene testing.
Immunohistochemistry (IHC) or microsatellite instability (MSI) screening for mismatch repair deficiency (dMMR)
on the tumor sample is recommended for individuals with colorectal or endometrial cancer, and can be considered for other cancers. These tests can be performed by a pathologist on archived tumor blocks from a surgical specimen.IHC and MSI are screening tests and, if positive, indicate that germline genetic testing is appropriate to determine which MMR gene is mutated. Increasingly, standard of care includes IHC for all newly diagnosed CRC and EC specimens.MSI maybe the screening method of choice in certain situations where the result could affect treatment decisions; patients with confirmed mismatch repair deficiency may be eligible for immunotherapy.
Depending on tumor screening results, additional tumor tests (BRAF V600Eanalysis and/or MLH1 promoter methylation analysis) may be indicated to further rule out Lynch syndrome, and in many cases, eliminate the need for germline genetic testing.
Germline molecular testing includes sequencing and deletion/duplication analysis ofMLH1, MSH2, MSH6, PMS2, and EPCAM. Often these genes are analyzed as part of a larger multigene hereditary cancer panel.
See the NCCN guidelines and GeneReviews below for a tumor and genetic testing strategy.
The NationalComprehensive Cancer Network (NCCN) guidelines list referral cirteria.
Meeting one or more of the criteria below warrants further risk assessment, genetic counseling and genetic testing as appropriate:
Early and increased surveillance (colonoscopy and endometrial biopsy, among other screening) and consideration of risk reducing interventions (such as preventive hysterectomy and oophorectomy) are recommended,as well as consideration of targeted therapeutics for afected patients. Published guidelines are available. See NCCN for more information about management.
There are other hereditary cancer syndromes that increase the risk for colorectal cancer, such as Familial Adenomatous Polyposis (FAP),MUTYH-Associated Polyposis (MAP), Peutz Jeghers syndrome, Juvenile Polyposis syndrome and Cowden syndrome. The presentation of these syndromes in a family may overlap with that of Lynch, but can sometimes be distinguished based on characteristic features, such as physical exam findings and polyp burden. In addition, a number of common genetic susceptibility variants are thought to increase colon cancer risk to a lesser extent than the MMR genes andEPCAM. While genetic testing with a multigene panel can detect variants for these risks as well as for Lynch syndrome, there are likely other genes that contribute to colon cancer which have not yet been identified. See GeneReviews for more information about the genetic differential diagnosis for LS.
American Society of Clinical Oncology (2021): Lynch Syndrome.
Medline/Genetics Home Reference (2021): Lynch Syndrome.
American College of Gastroenterology (2015): Clinical Guideline on Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes.
American College of Medical Genetics & National Society of Genetic Counselors (2014):Referral Indications for Cancer Predisposition Assessment. (see Addendum, 2019).
American College of Obstetrics and Gynecology (2019): https://www.sgo.org/wp-content/uploads/2012/09/2014-ACOG-bulletin.pdfCommittee Opinion #793. Hereditary Cancer Syndromes and Risk Assessment.
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009):Recommendations from the EGAPP Working Group: Genetic Testing Strategies in Newly Diagnosed Individuals with Colorectal Cancer Aimed at Reducing Morbidity and Mortality from Lynch Syndrome Relatives.
National Comprehensive Cancer Network (v.1.2023): Genetic/Familial High Risk Assessment: Colorectal (free registration required for access).
US Multi-Society Task Force (2015): Guidelines on Genetic Evaluation and Management of Lynch Syndrome.
Updated August 2023