Clinical and Molecular Features of Skin Malignancies in Muir-Torre Syndrome

Abstract

Background: We investigated the mutational landscape of skin tumors in patients with Muir-Torre Syndrome (MTS) a hereditary autosomal dominant mismatch repair disorder of increased cancer susceptibility, and examined mutations other than in the DNA mismatch repair (MMR) genes. Methods: This retrospective single-center case series included seven patients with the diagnosis of Muir-Torre Syndrome with precise medical history and family history. Mutational analysis of tumor samples Formalin-fixed paraffin-embedded tissue blocks of skin lesions associated with Muir-Torre Syndrome were used for further analysis. All skin tumors were analyzed with the Oncomine Comprehensive Assay v3 (Life Technologies), which includes 161 of the most relevant cancer driver genes. Results: Eleven skin neoplasms (nine sebaceous tumors, one melanoma, one cutaneous squamous cell carcinoma) were diagnosed in seven patients. In two patients, visceral malignancies preceded the diagnosis of the skin tumors and one patient was diagnosed with a visceral malignancy after a sebaceous tumor. History of familial cancer of Lynch Syndrome (LS) was reported in three patients. The most frequently detected mutation was in the MSH2 gene, followed by mutations in the NOTCH1/2 and TP53 gene. Conclusion, this study provides a molecular analysis of Muir-Torre Syndrome associated and non-associated skin tumors in patients with Muir-Torre Syndrome. Patients with sebaceous lesions should undergo microsatellite instability analysis and accurate evaluation of personal and family history to detect a possible Muir-Torre syndrome. As secondary malignancies may appear years after the first occurrence of sebaceous tumors, lifelong screening is mandatory.

Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series

“…After determining a cancer’s genetic aberrations, therapy targeted to the specific gene abnormality can be initiated. Although this analysis is not often used in the evaluation of Muir-Torre syndrome-associated sebaceous neoplasm to establish the diagnosis of Lynch syndrome, investigators have evaluated sebaceous skin tumors with next-generation sequencing to determine clinically actionable genes [ 14 , 17 ].…”

“…Mismatch repair gene mutations were identified in the sebaceous neoplasms of all the patients. Six patients had a mutation in the MSH2 gene, and one patient had a mutation in the MLH1 gene [ 14 ].…”

“…A third patient had sebaceous neoplasm with a NOTCH1 gene mutation. Mutations in 16 other genes were also noted only once in one of the nine sebaceous neoplasms [ 14 ].…”

“…They utilize immunohistochemistry staining, microsatellite instability testing, and next-generation sequencing of the paraffin-embedded tumor. In addition, blood, saliva, or normal skin can be used for germline evaluation [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Clinical Features and Prognosis of Young and Middle-Aged Adults With Skin Sebaceous Adenocarcinoma

“…27 Because secondary malignancies could appear years after the first occurrence of sebaceous adenocarcinoma, lifelong screening is mandatory for potential Muir–Torre syndrome population. 28 For SAC cohorts irrespective of age, only 3% of patients were suspected of Muir–Torre syndrome. 4 In this cohort, however, around every 1 in 5 nonelderly patients potentially suffered from Muir–Torre syndrome.…”