What are the diagnostic tests for Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC)?

From the Guidelines

Testing for Lynch syndrome should involve a combination of genetic testing, family history assessment, and tumor analysis, starting with immunohistochemistry (IHC) or microsatellite instability (MSI) testing on tumor tissue to identify individuals with deficient DNA mismatch repair, as recommended by the most recent guidelines 1. The process of testing for Lynch syndrome typically begins with a detailed family history evaluation to identify patterns of cancer that might suggest Lynch syndrome, such as multiple family members with colorectal, endometrial, or other related cancers, especially at young ages.

• Key steps in testing for Lynch syndrome include:
  • Family history assessment to identify high-risk individuals
  • Tumor analysis using IHC or MSI testing to detect deficient DNA mismatch repair
  • Genetic testing for mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes associated with Lynch syndrome
  • Consideration of testing for at-risk family members if a mutation is identified According to the guidelines from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG) published in 2020 1, IHC or MSI testing should be used to identify tumors with deficient DNA mismatch repair, and to guide further sequential testing for LS. The use of colonoscopic biopsies as the preferred source material for tumor MMR testing is also recommended 1. Early detection of Lynch syndrome is crucial because it allows for enhanced cancer surveillance, including more frequent colonoscopies starting at a younger age, as well as screening for other Lynch-associated cancers, which can significantly reduce cancer-related mortality. It is essential to follow the most recent guidelines and recommendations for testing and management of Lynch syndrome, as outlined in the guidelines from reputable organizations such as the BSG/ACPGBI/UKCGG 1.

From the Research

Testing for Lynch Syndrome

To test for Lynch syndrome, several methods can be employed, including:

• Microsatellite instability (MSI) testing to identify tumor mismatch repair deficiencies 2
• Immunohistochemical testing to detect the presence or absence of mismatch repair proteins in tumor tissue 2, 3
• Germline genetic testing for mutations in the MLH1, MSH2, MSH6, and PMS2 genes, as well as deletions of the EPCAM gene 4, 5, 6
• Universal screening approaches, which involve testing all new diagnoses of colorectal or endometrial cancers for Lynch syndrome 4, 2

Recommended Testing Approach

The recommended approach to testing for Lynch syndrome involves:

• Testing all patients with colorectal or endometrial cancer for MSI and/or mismatch repair deficiency 4, 2
• Offering genetic counseling and germline testing to patients with cancer who test positive for MSI or mismatch repair deficiency 4
• Considering a gene-specific approach to disease management, with potential cancer-preventing vaccines in development 4

Importance of Early Detection

Early detection of Lynch syndrome is crucial, as it allows for:

• Implementation of preventive measures, such as high-quality 2-yearly colonoscopy and prophylactic gynaecological surgery 4
• Improved patient outcomes through early diagnosis and treatment of associated cancers 4
• Identification of family members who may also be at risk of developing Lynch syndrome-associated cancers 4, 3