Muir-Torre syndrome (MTS), a rare variant of the hereditary non polyposis colorectal cancer syndrome, is an autosomal dominant genodermatosis characterised by coincidence of sebaceous gland neoplasms (sebaceous adenoma, epithelioma, or carcinoma) and at least one internal malignancy. The underlying cause of MTS is a germline mutation in DNA mismatch repair genes MSH2, MLH1 and MSH6. We report the case of a 52-year-old caucasian woman with the development of metachronous colon cancer at the age of 38 years, uterine cancer at the age of 43 years, and unique occurrence of synchronous gastric and sebaceous carcinomas related to germline point mutation c. 2194A>T in the last exon of MLH1 gene, resulting in truncated protein in C-terminal region p. Lys732X due to premature stop codon. This mutation, not previously reported in MTS, disrupts the function of MutL complexes presumably by preventing the interaction with PMS1/PMS2 and impairing the endonuclease active site. This case points out the importance of sebaceous neoplasia, especially sebaceous adenocarcinoma, as cutaneous markers of MTS for timely implementation of cancer screening programs.

2nd Department of Internal Medicine 3rd Faculty of Medicine Charles University Prague

2nd Department of Internal Medicine 3rd Faculty of Medicine Charles University Prague ; Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague

Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague

Department of Pathology 3rd Faculty of Medicine Charles University Prague

Institute of Biology and Medical Genetics 1st Faculty of Medicine and General Teaching Hospital Charles University Prague

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Muir EG, Bell AJ, Barlow KA. Multiple primary carcinomata of the colon, duodenum, and larynx associated with kerato-acanthomata of the face. Br J Surg. 1967;54:191–195. PubMed

Torre D. Multiple sebaceous tumors. Arch Dermatol. 1968;98:549–551. PubMed

Ponti G, Losi L, Pedroni M, Lucci-Cordisco E, Di Gregorio C, Pellacani G, Seidenari S. Value of MLH1 and MSH2 mutations in the appearance of Muir-Torre syndrome phenotype in HNPCC patients presenting sebaceous gland tumors or keratoacanthomas. J Invest Dermatol. 2006;126:2302–7. PubMed

South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A. The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst. 2008;100:277–81. PubMed

Kolodner RD, Hall NR, Lipford J, Kane MF, Rao MR, Morrison P, Wirth L, Finan PJ, Burn J, Chapman P. Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics. 1994;24:516–26. PubMed

Bapat B, Xia L, Madlensky L, Mitri A, Tonin P, Narod SA, Gallinger S. The genetic basis of Muir-Torre syndrome includes the hMLH1 locus. Am J Hum Genet. 1996;59:736–9. PubMed PMC

Mangold E, Rahner N, Friedrichs N, Buettner R, Pagenstecher C, Aretz S, Friedl W, Ruzicka T, Propping P, Rutten A, Kruse R. MSH6 mutation in Muir-Torre syndrome: could this be a rare finding? Br J Dermatol. 2007;156:158–62. PubMed

Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116:1453–6. PubMed

Buhard O, Cattaneo F, Wong YF, Yim SF, Friedman E, Flejou JF, Duval A, Hamelin R. Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors. J Clin Oncol. 2006;24:241–51. PubMed

Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 2007;67:4595–604. PubMed

Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell. 2006;126:297–308. PubMed

Peltomaki P, Vasen H. Mutations associated with HNPCC predisposition-Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers. 2004;20:269–76. PubMed PMC

Kruse R, Ruzicka T. DNA mismatch repair and the significance of a sebaceous skin tumor for visceral cancer prevention. Trends Mol Med. 2004;10:136–41. PubMed

Hajer J, Kepelova A, Zadorova Z, Kment M. Two novel germline mutations (Y548X and K732X) of the MLH1 gene in Czech patients with hereditary nonpolyposis colorectal cancer. Hum Mutat. 2000;16:181. PubMed

Pang Q, Prolla TA, Liskay RM. Functional domains of the Saccharomyces cerevisiae Mlh1p and Pms1p DNA mismatch repair proteins and their relevance to human hereditary nonpolyposis colorectal cancer-associated mutations. Mol Cell Biol. 1997;17:4465–73. PubMed PMC

Gueneau E, Dherin C, Legrand P, Tellier-Lebegue C, Gilquin B, Bonnesoeur P, Londino F, Quemener C, Le Du MH, Marquez JA, Moutiez M, Gondry M, Boiteux S, Charbonnier JB. Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site. Nat Struct Mol Biol. 2013;20:461–8. PubMed

Akhtar S, Oza KK, Khan SA, Wright J. Muir-Torre syndrome: case report of a patient with concurrent jejunal and ureteral cancer and a review of the literature. J Am Acad Dermatol. 1999;41:681–6. PubMed

Shellenberger MJ, Deivert DE, Komar MJ. Genes are more than skin deep: a case of Muir-Torre syndrome. Gastrointest Endosc. 2008;68:608–10. PubMed

Tanyi M, Olasz J, Lukacs G, Tanyi JL, Toth L, Antal-Szalmas P, Ress Z, Buban T, Andras C, Damjanovich L. A new mutation in Muir-Torre syndrome associated with familiar transmission of different gastrointestinal adenocarcinomas. Eur J Surg Oncol. 2009;35:1128–30. PubMed

Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Jarvinen HJ, Myrhøj T, Sunde L, Wijnen JT, Lynch HT. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008;123:444–9. PubMed PMC

Entius MM, Keller JJ, Drillenburg P, Kuypers KC, Giardiello FM, Offerhaus GJ. Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome. Clin Cancer Res. 2000;6:1784–9. PubMed