In this study, we report a 74-year-old man with known Muir-Torre syndrome with confirmed MSH2 germline mutation, diagnosed with pleomorphic liposarcoma of the right buttock in a previous radiation field.
Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: establishment of immunohistochemical analysis as a screening test.
Haplotype analysis showed that the kindreds C and V+Va (both from northeastern Italy, both displaying clinical features of the Muir-Torre syndrome) shared a seven-locus haplotype, indicating that the MSH2 1-6 deletion is probably a founder mutation.
Having a high probability for MSI, she was found to be heterozygous for a germline point mutation in MSH2 gene, where a pathologic variant, c.1165C > T (p.Arg389*), determined by sequencing confirmed Muir-Torre syndrome (MTS).
Mutations reported to cause Muir-Torre syndrome (MTS) have previously been reported in the mismatch repair genes MLH1 and MSH2 and more recently, in MYH [1].
Most examples of hereditary non-polyposis cancer syndrome (Lynch syndrome), including the Muir-Torre syndrome, are associated with microsatellite instability (MSI) and germline mutations in mismatch repair genes-most commonly MLH1 or MSH2.
Most examples of hereditary non-polyposis cancer syndrome (Lynch syndrome), including the Muir-Torre syndrome, are associated with microsatellite instability (MSI) and germline mutations in mismatch repair genes-most commonly MLH1 or MSH2.
Muir-Torre syndrome is usually inherited in an autosomal dominant fashion and associated with mutations in the mismatch repair genes, predominantly in MLH1 and MSH2 genes.
Families who carried the c.942+3A>T MSH2 gene mutation had a higher frequency of Muir-Torre syndrome than families who carried other mutations in the MSH2 gene (75% vs 25%; P = .026).
These methods have been used to analyze two large HNPCC kindreds exhibiting features of the Muir-Torre syndrome and demonstrate that cancer susceptibility is due to the inheritance of a frameshift mutation in the MSH2 gene in one family and a nonsense mutation in the MSH2 gene in the other family.
We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.
All 10 sporadic periocular sebaceous carcinomas maintained strong staining of the 4 mismatch repair genes, while tumor from the patient with Muir-Torre syndrome showed loss of staining for the mismatch repair genes MSH2 and MSH6.
Thus, we could show in a sample of sebaceous tumors from patients with genetically proven Muir-Torre syndrome that loss of heterozygosity most probably is not the preferred mode of somatic inactivation of the second MSH2 allele.