Ollila 25_8

A majority of families with hereditary nonpolyposis colorectal cancer (HNPCC) are attributable to germline mutations in three DNA mismatch repair (MMR) genes, MLH1, MSH2 and MSH6. However, the clinical phenotype appears to reflect a complex interplay between the predisposing mutation and putative constitutional and somatic modifiers. Certain MMR gene mutations predispose to combined occurrence of cutaneous sebaceous gland neoplasms and visceral malignancies, which is known as MuirTorre syndrome (MTS) and regarded as a phenotypic variant of HNPCC. The sebaceous tumors associated with MTS appear in many patients before visceral malignancies providing important predictability of HNPCC-related integral cancers in mutation carriers. Since most sebaceous skin tumors are, however, sporadic, the contribution of non-truncating mutations found in skin cancer patients is difficult to interpret and genetic assessment of MTS requires a functional test. Here, we studied the repair efficiency of the two MSH2 missense mutations, L187P and C697F, found in HNPCC families including a few mutation carriers with sebaceous skin tumors. Both mutations were completely deficient in an MMR assay, which together with tumor findings suggested their predisposing role in both internal and skin malignancies in the families. Introduction The same germline mutations in DNA mismatch repair (MMR) genes that have a high penetrance in colon malignancies may in some circumstances predispose to cutaneous sebaceous gland tumors and keratoacanthomas. This combined occurrence of at least one visceral neoplasm and at least one sebaceous gland skin tumor in a patient is known as Muir-Torre syndrome (MTS) (1,2). Because of its common genetic predisposition, MTS is currently considered as a subphenotype of hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch syndrome II) (3-7). A recent study on MTS among patients with sebaceous tumors and keratoacanthomas demonstrated that, while the vast majority of sebaceous tumors develop as sporadic forms, the sebaceous tumors which were associated with MTS were multiple and recurrent. Moreover, they showed an early onset and appeared in 60% of patients before visceral malignancies (8), explaining why sebaceous neoplasms are frequently diagnosed without concomitant visceral tumors irrespective of linkage to HNPCC. On the other hand, a probable explanation for the low MTS frequency in known HNPCC kindreds is that skin manifestations are so rare or too minor to be recognized. Consequently, the recognition and diagnosis of MTS is difficult and requires both clinical and molecular assessment. A defect in the MMR mechanism results in multiple somatic mutations affecting mainly small repeated sequences such as microsatellites and leads to high microsatellite instability (MSI-H). MSI-H phenotype is a hallmark of HNPCC tumors, including MTS-associated skin tumors (7,9). Actually, sebaceous neoplasms have been shown to be the tumors with the highest frequency of MSI-H (10). Unfortunately, a reliable assessment of MTS cannot be solely based on MSI-H phenotype in skin cancer. Most sebaceous tumors seem to be sporadic (8) and an alternative explanation for MSI-H in a tumor may well be a somatic inactivation of the MMR system, e.g. by MLH1 promoter hypermethylation that is a frequent INTERNATIONAL JOURNAL OF ONCOLOGY 28: 149-153, 2006 149 The importance of functional testing in the genetic assessment of Muir-Torre syndrome, a clinical subphenotype of HNPCC SAARA OLLILA1, ROSLYN FITZPATRICK2, LAURA SARANTAUS1, REETTA KARIOLA1, INGRID AMBUS3, LEA VELSHER3, EUGENE HSIEH4, METTE KLARSKOV ANDERSEN5, TIINA E. RAEVAARA1, ANNE-MARIE GERDES5, ELISABETH MANGOLD6, PÄIVI PELTOMÄKI7, HENRY T. LYNCH8 and MINNA NYSTRÖM1 1Department of Biological and Environmental Sciences, Genetics, University of Helsinki, Helsinki, Finland; 2Toronto, Ontario, Canada; 3Genetics Program, North York General Hospital; 4Department of Anatomic Pathology, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, Canada; 5Clinical Genetics Department of KKA, Odense University Hospital, Odense C, Denmark; 6Institute of Human Genetics, University of Bonn, Germany; 7Department of Medical Genetics, University of Helsinki, Helsinki, Finland; 8Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE, USA Received August 25, 2005; Accepted October 3, 2005 _________________________________________ Correspondence to: Dr Minna Nyström, Department of Biological and Environmental Sciences, Genetics, University of Helsinki, Viikinkaari 5, FI-00014 Helsinki, Finland E-mail: [email protected]