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Detecting Mismatch Repair Gene Mutations: Applications in Dermatology

DETECTING MISMATCH REPAIR GENE MUTATIONS: APPLICATIONS IN DERMATOLOGY
Mismatch repair (MMR) genes play a critical role in maintaining DNA stability through the process of cell replication. Several such MMR genes have been identified, most notably, hMLH1, hMSH2, hMSH3, PMS2,and hMSH6. Antibodies specific for antigens associated with the protein products of many of these genes have been developed. Because mutated genes may lose the ability to form these proteins, such techniques provide an indirect method of detecting MMR gene mutations through immunohistochemical methods. The lack of nuclear staining amongst the cells in question denotes an absence of MMR gene protein product. This in turn connotes a mutation of the respective MMR gene. Testing for hMLH1 and hMSH2 is performed by the Immunohistochemistry Division of ProPath Laboratory.

Mutations in MMR genes, leading to a deficiency in their respective protein products, have been linked to the development of a wide range of neoplastic processes. Amongst solid tumors, MMR gene mutations have been implicated in the development of a portion of colorectal carcinomas, endometrial carcinomas, urothelial carcinomas, and squamous cell carcinomas of the head and neck. Similar findings have been reported in relation to the oncogenesis and progression of certain hematopoietic malignancies.

Conditions manifesting in the skin have also been linked to alterations in MMR gene function. In recent years, germ-line mutation in MMR genes have been recorded in patients with Muir-Torre syndrome (MTS). MTS is an autosomal dominant condition chracterized by sebaceous tumors (fig. 1) and visceral malignancies. Keratoacanthomas, epidermal (follicular) cysts, and colonic polyps may also be a part of this unusual syndrome.  

 Fig. 1. Sebaceous adenoma arising in a person with Muir-Torre phenotype
(2X).

Although the associated visceral malignancies are most often gastrointestinal in type, many of the other solid and hematopoietic malignancies listed above have also been described in persons with MTS. Because of this close association between easily biopsied cutaneous neoplasms and potentially terminal visceral disease, testing for MMR gene mutations in skin biopsies of persons at risk for Muir-Torre phenotype may be of profound utility as a method of screening (Fig. 2, Fig. 3). Such testing may be employed to effectively diagnose MTS in patients on whom relatively few skin manifestations are seen. It should be noted that in some instances, persons with bonifide MTS may possess only a single sebaceous tumor.

The significance of MMR gene mutations to the field of dermatology extends far beyond its relation to MTS. Investigators have recently described a progression of microsatellite instability caused by MMR gene mutations in melanocytic neoplasms of skin. Palmieri et al. were unable to identify MMR gene mutations in any benign nevi in their series; however, found such mutations in 9% of dysplastic nevi, 11% of primary melanomas, and 21% of melanoma metastases. They concluded that such mutations contributed to the progression of a subset of melanomas. Similar findings have been published using Immunohistochemistry to assess for hMLH1, hMSH2, and hMSH6-related antigens.

 

Although in its earliest stages, such research holds extraordinary promise as an adjunct to histopathology in assessing difficult or “borderline” cases of melanocytic neoplasia. More importantly, such techniques may be the first step in what will lead to less subjective, molecular definitions of benign and malignant melanocytic proliferations.

References
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11. Palmieri G, et al. Assessment of genetic instability in melanocytic skin lesions through microsatellite analysis.. Melanoma Res. 13:167-170, 2003.
12. Hussein MR, et al. Alterations of mismatch repair protein expression in benign melanocytic nevi, melanocytic dysplastic nevi, and cutaneous malignant melanomas. Am J Dermatopathol 23:308-314, 2001.