For Residents

The DNA Mismatch Repair System in Sebaceous Tumors: An Update on the Genetics and Workup of Muir-Torre Syndrome

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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.



It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.1 If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.2

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,3 colorectal adenocarcinomas,4 keratoacanthomas,5 and other visceral malignancies.6 Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.5 These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.7 This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).8 This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.9 Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.10 Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.9

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.11 Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.12 These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.13 Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,14 which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.15 Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.16

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.17 It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.18

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.19 Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.20 Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.21


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