What genetic testing is recommended for Muir-Torre syndrome, specifically which genes (Genes) should be tested?

Genetic Testing for Muir-Torre Syndrome

For patients with suspected Muir-Torre syndrome, genetic testing should include MLH1, MSH2, MSH6, and PMS2 genes, with MSH2 being the most commonly mutated gene in this condition. 1

Understanding Muir-Torre Syndrome

Muir-Torre syndrome (MTS) is a rare variant of Lynch syndrome characterized by:

• Sebaceous neoplasms (sebaceous adenomas, sebaceous carcinomas, keratoacanthomas)
• Internal malignancies (colorectal, endometrial, genitourinary, and other Lynch syndrome-associated cancers)

MTS is caused by germline mutations in mismatch repair (MMR) genes, leading to microsatellite instability (MSI) in tumor DNA.

Recommended Genetic Testing Approach

Primary Testing Strategy:

1. Test all four MMR genes:
   • MSH2 (most commonly mutated in MTS)
   • MLH1
   • MSH6
   • PMS2
   • EPCAM (deletions affecting MSH2 expression)

Testing Prioritization:

If sequential testing is needed due to cost or other factors:

• First-line testing: MSH2 (highest yield in MTS)
• Second-line testing: MLH1
• Third-line testing: MSH6 and PMS2 1

Testing Based on IHC Results:

If immunohistochemistry (IHC) has been performed on tumor tissue:

• Target genetic testing to the specific gene(s) with absent protein expression
• If MSH2 protein is absent, test MSH2 and EPCAM
• If MLH1 protein is absent, test MLH1 (after ruling out BRAF V600E mutation and MLH1 promoter hypermethylation)
• If MSH6 or PMS2 proteins are absent, test the corresponding genes 1

Important Clinical Considerations

Diagnostic Criteria:

• MTS should be suspected in patients with sebaceous neoplasms and personal or family history of Lynch syndrome-associated cancers 1
• Even a single sebaceous neoplasm should prompt consideration of genetic testing 2

Testing Limitations:

• IHC and MSI testing can produce false negatives in MTS cases 2
• Some missense mutations may result in retained protein staining despite functional deficiency 1
• Approximately 10% of Lynch syndrome colorectal cancers show intact MMR protein staining on IHC 1

Genotype-Phenotype Correlations:

• MSH2 mutations are most common in MTS (unlike general Lynch syndrome where MLH1 and MSH2 are more equally represented) 3, 4
• MSH2 mutation carriers have a higher rate of urinary tract tumors (6%) 1
• PMS2 and MSH6 mutations have lower penetrance compared to MLH1 and MSH2 5

Follow-up Recommendations

For patients with confirmed MTS:

• Colonoscopy every 1-2 years beginning at age 20-25 or 10 years younger than the youngest diagnosis in the family 1, 3
• Annual skin examination 3
• For women: endometrial cancer screening starting at age 30-35 5
• Consider screening for other Lynch syndrome-associated cancers based on family history 1

Family Testing:

• First-degree relatives should be offered genetic testing for the specific mutation identified in the proband 1
• If a first-degree relative is unavailable or unwilling to be tested, more distant relatives should be offered testing 1

Pitfalls to Avoid

• Don't rely solely on clinical criteria: The Mayo Muir-Torre syndrome risk score algorithm cannot always reliably determine which patients should have germline testing 2
• Don't exclude MTS based on negative IHC: Some mutations result in functionally deficient but immunohistochemically detectable proteins 2, 4
• Don't miss MSH6 mutations: These may be overlooked due to later age of onset and lower penetrance 5
• Don't rely solely on MSI testing: MSI may be negative in some MTS-associated cancers, especially non-gastrointestinal malignancies 1