Lynch Syndrome Factsheet

Clinical Features

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, including endometrial, ovarian, gastric, small bowel, bladder, urothelial, pancreas, biliary tract, prostate, breast, brain (usually glioblastoma), 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 associated with Lynch syndrome mutations

 

MLH1

MSH2

MSH6

PMS2

General population

Colorectal

46-49%

43-52%

15-44%

12-20%

4.5%

Endometrial

43-57%

21-57%

17-46%

Up to 15%

2.7%

Breast

Up to 17%

Not increased

Not increased

NE

13%

Ovarian

5-20%

10-38%

Up to 11%

NE

1.3%

Gastric

5-7%

Up to 16%

Up to 5%

NE

<1%

Pancreas

6%

NE

NE

NE

1.5%

Bladder

2-4%

4-17%

Not increased

NE

2.5%

Biliary tract

2-4%

Not increased

NE

NE

<1%

Urothelial

0.2-5%

2-18%

0.7-7%

NE

<1%

Small bowel

0.4-11%

1-10%

Up to 3%

NE

<1%

Prostate

Up to 17%

30-32%

Up to 5%

NE

11.6%

Brain/CNS

NE

NE

Not reported

Not reported

<1%

NE: Not well-established

Adapted from: NCCN v.3.2019 (December 2019)

Prevalence of LS

About 1-3% of colorectal cancers and 0.8-1.4% of endometrial cancers can be attributed to LS. An estimated 1 in 300-440 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.

Diagnosis

An individual should have a mutation identified through molecular testing of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or EPCAM gene, or meet the clinical criteria below.

Clinical Criteria

The Amsterdam II criteria define the minimum requirements for a clinical diagnosis of Lynch syndrome:

  • There should be at least three relatives with a Lynch-associated cancer (cancer of the colorectum, endometrium, small bowel, ureter or renal pelvis)
  • Familial adenomatous polyposis should be excluded
  • Tumors should be verified by pathological examination

The Amsterdam criteria have high specificity for LS, but low sensitivity. Not all families with LS will meet these criteria. 

Genetics & Inheritance

LS is caused by a mutation in a mismatch repair (MMR) gene, which includes MLH1, 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 syndrome mutations should be aware that if they have a child with another person who also has Lynch syndrome, the child has a 25% chance of having Biallelic Mismatch Repair Deficiency (BMMRD), characterized by brain, blood, gynecological, and certain pediatric cancers.

Clinical Testing

Clinical testing options include tumor analysis with immunohistochemistry (IHC) and/or microsatellite instability (MSI) and molecular analysis of the MLH1, 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 targeted gene testing based on tumor results. 

Tumor Analysis

Immunohistochemistry (IHC) or microsatellite instability (MSI) testing on the tumor sample is recommended for individuals with colorectal or endometrial cancer. These tests can be performed by a pathologist on archived tumor blocks from a surgical specimen.

  • IHC testing can detect the presence or absence of the protein products of the mismatch repair genes. A missing protein suggests a mutation in the gene that codes for that protein. 83% of individuals with LS have abnormal IHC results.
  • MSI testing can detect an abnormal number of microsatellite repeats, which indicates that the cancer more likely arose from cells with defective MMR genes. A result of “MSI-high” means that a high number of unstable microsatellite repeats were found. 90% of individuals with LS have MSI-high results. 

IHC and MSI are screening tests and, if positive, indicate that germline genetic testing is appropriate to determine which MMR gene is mutated. Increasingly, it is becoming standard of care for IHC to be performed on all newly-diagnosed CRC and select 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 V600E analysis 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. 

Genetic Testing

Germline molecular testing includes sequencing and deletion/duplication analysis of MLH1, MSH2, MSH6, PMS2, and EPCAM. Molecular testing is most informative and cost effective when performed after initial tumor screening using IHC/MSI. 

See the NCCN guidelines and GeneReviews below for a suggested tumor and genetic testing strategy.

Genetic Testing and Referral Criteria

The Amsterdam II criteria define the minimum requirements for a clinical diagnosis of Lynch syndrome. These criteria have high specificity for LS, but low sensitivity. Not all families with LS will meet these criteria. For up-to-date criteria for evaluation for Lynch syndrome, please refer to National Comprehensive Cancer Network (NCCN) guidelines.

Meeting one or more of the criteria below warrants further risk assessment, genetic counseling and genetic testing as appropriate:

  • Known LS mutation in family
  • Absent expression of MMR proteins on IHC or MSI-H in tumor
  • An individual with a >5% risk of having a LS gene mutation using predictive models
  • 3 or more individuals with CRC or LS-associated cancers at any age
  • 2 individuals with CRC or LS-associated cancers, with at least one diagnosed before age 50 years
  • 1 or more individuals with
      • CRC diagnosed at a younger than usual age (< 50 years), or
      • Two primary cancers: CRC or endometrial cancer and a LS-associated cancer, or
      • CRC with MSI-high histology, or
      • Somatic tumor testing suggesting hereditary cancer or a known pathogenic variant

Management

Increased surveillance (colonoscopy and endometrial biopsy, among other screening) and consideration of risk reducing interventions (such as chemoprevention and 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.

Other Genes that Contribute to Colon Cancer

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 and EPCAM. 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. 

Select Guidelines & References

Resources

American Society of Clinical Oncology (2020): Lynch Syndrome.

GeneReviews (2018): Lynch Syndrome.

Guidelines

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.

American College of Obstetrics and Gynecology (2014): Practice Bulletin #147. Lynch Syndrome.

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.3.2019): 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 May 2020