The DNA Mismatch Repair System in Sebaceous Tumors: An Update on the Genetics and Workup of Muir-Torre Syndrome
Mutations in the genes encoding the DNA mismatch repair (MMR) are identified in most sebaceous neoplasms. Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in the MMR system. This article describes the DNA MMR system and its implication in sebaceous tumors as well as discusses the recent recommendations for screening for Muir-Torre syndrome (MTS) in patients presenting with sebaceous tumors.
Resident Pearls
- When patients present with a solitary sebaceous tumor, there is a high likelihood they have Muir-Torre syndrome (MTS) and thus are at a high risk to develop visceral malignancies.
- It is important to perform further testing using immunohistochemistry for DNA mismatch repair proteins and microsatellite instability gene analysis in some cases to confirm the diagnosis of MTS and to perform the appropriate cancer screening tests.
Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.23,35,36
,If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.13
One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.37 As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.
Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.38
It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.
Final Thoughts
Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.19
