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Health Professionals:
More About the EGAPP™ Lynch Syndrome Recommendation

This page contains more information about the EGAPP Lynch syndrome recommendation for health professionals.

For more information about genetic testing for Lynch syndrome that is not part of the EGAPP recommendation, see More About Genetic Testing for Lynch Syndrome.

 

EGAPP™ Evidence Review at a Glance

Testing Approach Application Quality of Evidence
Adequacy of information to address:
Overall Recommendation*
Analytic Validity Clinical Validity Clinical Utility
DNA analysis of mismatch repair (MMR) genes: (MLH1, MSH2, MSH6, PMS2) Diagnostic Testing Adequate Convincing Adequate Sufficient evidence to recommend use for the benefit of relatives
Microsatellite Instability (MSI) Preliminary (Screening) Test Convincing / Adequate
Immunohisto-chemistry (IHC) Preliminary (Screening) Test Convincing / Adequate
Methylation Status (BRAF V600E mutation) Preliminary (Screening) Test (Supplemental to IHC) Adequate

*Overall recommendation was decided on the basis of a) evidence indicating moderate level of net health benefits to relatives, and b) contextual factors.

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Considerations for Practice

Note: See Contextual Factors Identified by EGAPP™ for more information.

  • All patients with a new diagnosis of colorectal cancer (regardless of age or family history) should be offered counseling and educational materials regarding genetic testing for Lynch syndrome. 
    • The primary benefit will be the identification of relatives who also carry a gene mutation for Lynch syndrome. Affected relatives can be offered appropriate screening beginning at age 20-25.
  • Colonoscopy every one to two years is recommended for these patients and their relatives who test positive for Lynch syndrome beginning at age 20-25 years. Although there is not enough research to indicate that colorectal cancer due to Lynch syndrome should be treated differently than non-Lynch related colorectal cancer, individuals with Lynch syndrome are at increased risk for additional cancers and second primary colon tumors.
  • Individuals with colorectal cancer should be offered genetic testing even if there are no other family members with Lynch syndrome cancers. This is because family history was found to be less useful as a first step than strategies involving tumor testing in identifying Lynch syndrome in individuals with colorectal cancer. However, family history may still be an important decision tool for identifying individuals in the general population for referral to genetic counseling services to evaluate risk for hereditary colorectal cancer.

See More Considerations for Practice for additional information that is not part of the EGAPP™ recommendation.

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Testing Approaches

Several testing approaches are potentially effective for identifying Lynch syndrome. DNA analysis has the highest sensitivity and specificity, but is also the most expensive. Most protocols directed at screening unselected colon cancers begin with preliminary testing of tumor tissue by MSI and/or IHC (with or without BRAF mutation).

  • Diagnostic testing: Typically performed on blood; identifies an inherited mutation in one of the Lynch syndrome genes.
    • DNA analysis (gene sequencing, deletion/duplication testing) for the mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2.
  • Preliminary (Screening) Tests: Performed on tumor tissue; does not identify Lynch (MMR) gene mutations, but is used to guide subsequent diagnostic testing via DNA analysis.
    • MSI testing of tumor tissue: those with high instability either proceed to DNA analysis for MLH1, MSH2, MSH6, and PMS2 or to IHC testing.
    • IHC testing of tumor tissue: those with negative staining would proceed to DNA analysis of the gene/genes indicated.
    • Modification of Strategy 3, such that tumor tissue of patients with negative staining for MLH1 on IHC is tested for the BRAF V600E mutation to determine methylation status.  If the BRAF mutation is not found, the individual continues on for MLH1 DNA analysis.



Contextual Factors Identified by EGAPP

  • Due to limited benefit to the colorectal cancer (CRC) patient, informed consent before microsatellite instability (MSI) or immunohistochemistry (IHC) testing is recommended.
  • There is no substantial evidence to show that identifying Lynch syndrome through routine genetic testing would lead to adverse psychological outcomes.
  • Evidence shows that there are relatively high levels of counseling and testing uptake among relatives and adherence to screening if patient is mutation positive.

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Research Gaps Identified by EGAPP

The EGAPP™ working group identified the need for research to address the following:

  • Better quality research regarding analytical validity of testing and laboratory proficiency testing;
  • Better quality studies evaluating clinical validity of various testing strategies;
  • Higher quality studies assessing clinical outcomes/clinical utility, effectiveness of screening;
  • Cost-effectiveness analyses to address testing strategies and impact on relatives
    (see More Considerations for Practice for additional information that is not part of the EGAPP™ recommendation);
  • Studies to assess whether the clinical care and screening of CRC patients with Lynch syndrome should be altered.

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For more information about genetic testing for Lynch syndrome that is not part of the EGAPP recommendation, see More About Genetic Testing for Lynch Syndrome.


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