MUIR-TORRE PHENOTYPE HAS A FREQUENCY OF DNA MISMATCH-REPAIR GENE-MUTATIONS SIMILAR TO THAT IN HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER FAMILIES DEFINED BY THE AMSTERDAM CRITERIA

Muir-Torre syndrome (MTS) is an autosomal dominant disease defined by the coincidence of at least one sebaceous skin tumor and one internal malignancy About half of MTS patients are affected by colorectal cance r. In a subgroup of MTS patients the disease has an underlying DNA mis match-repair (MMR) defect and thus is allelic to hereditary nonpolypos is colorectal cancer (HNPCC). The purpose of this study was to examine to what extent germ-line mutations in DNA MMR genes are the underlyin g cause of the MTS phenotype. We ascertained 16 MTS patients with seba ceous skin tumors and colorectal cancer, and we examined their skin an d visceral tumors for microsatellite instability. All the patients exh ibited high genomic instability in at least one tumor. The search for germ-line mutations in the hMSH2 and hMLH1 genes in 13 of the MTS pati ents revealed truncating mutations in 9 (69%): eight mutations in the hMSH2 gene and one in the hMLH1 gene. This is the first systematic sea rch for germ-line mutations in patients ascertained on the basis of se baceous skin tumors. Our results indicate that (1) MTS patients exhibi t significantly more mutations in the hMSH2 gene than in the hMLH1 gen e; and (2) the subpopulation of MTS patients who are also affected by colorectal cancer, irrespective of family history and age at onset of tumors, may have a likelihood for an underlying DNA MMR defect similar to that for patients with a family history fulfilling the strict clin ical criteria for HNPCC.