A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome.

M uir-Torre syndrome (MTS; MIM 158320) is an autosomal dominant predisposition to skin tumours and various internal malignancies. Clinical criteria for a diagnosis of MTS are the synchronous or metachronous occurrence of at least one sebaceous gland neoplasia and at least one internal neoplasm in a patient (regardless of the family history). 2 The sebaceous gland neoplasias comprise adenomas, epitheliomas (sebaceomas), and carcinomas. In contrast, the frequent sebaceous gland hyperplasia is not indicative of MTS. 3 According to Schwartz and Torre, the sebaceous neoplasias precede the internal neoplasias or are concurrent with them in 41% of MTS patients. As sebaceous gland neoplasias are rare, MTS should always be suspected when a sebaceous tumour has been diagnosed. Cystic sebaceous neoplasia is probably the most sensitive marker for this tumour predisposition syndrome. 4–6 Colorectal cancer is by far the most common internal malignancy in MTS patients. The spectrum of internal malignancies in MTS is similar to the various tumour entities observed in hereditary non-polyposis colorectal cancer (HNPCC; MIM 114500). HNPCC is an autosomal dominant cancer predisposition syndrome characterised by early onset of colorectal cancer and other associated tumours. 9 Several genes underlying HNPCC which are involved in DNA mismatch repair (MMR) have been identified within the last decade. Germline mutations in the DNA MMR genes were detected in a high proportion of MTS patients, demonstrating that MTS most often represents a phenotypic variant of HNPCC. 15 Due to the underlying genetic mechanisms of tumourigenesis, tumours of these MTS patients exhibit high microsatellite instability (MSI-H), the characteristic feature of HNPCC tumours. Microsatellite analysis in tumour tissue of MTS patients therefore provides a useful tool to pre-select patients for mutation analysis in DNA MMR genes. Immunohistochemical testing for expression of the MSH2 and MLH1 proteins in skin tumour tissue is an alternative reliable screening method with high predictive value for the diagnosis of DNA mismatch repair deficient MTS (HNPCC). 18 A diagnosis of HNPCC in an MTS patient is of major importance for both the patient and his/her close relatives, as all family members who inherited the DNA MMR defect have a substantially higher risk for HNPCC malignancies and should therefore undergo regular cancer surveillance examinations. Identification of the underlying DNA MMR germline mutation in the index patient enables predictive genetic testing of his/her family members at risk. To date, DNA MMR gene mutations in MTS patients have been reported in both the MSH2 and MLH1 genes. While the proportions of MLH1 and MSH2 mutations in HNPCC are almost equal (ICG-HNPCC mutation database, http:// www.nfdht.nl), in MTS the vast majority of mutations have been identified in MSH2. This suggests a genotype correlation for the Muir-Torre phenotype among HNPCC patients. The aim of this study was to further support this genotype– phenotype correlation in HNPCC. We determined the DNA MMR mutation spectrum in a large MTS patient sample after pre-selection by examination for MSI and immunostaining in tumour tissue. For this purpose we extended our previously reported sample of 15 MTS patients 15 19 20 to a total of 41