Abstract for presentation at 11th International Congress of Human Genetics

Analysis of MSH2 missense mutations predisposing to HNPCC and Muir-Torre syndrome

  • Saara Ollila, Department of Biological and Environmental Sciences, Genetics, University of Helsinki, Helsinki, Finland., Finland
  • Roslyn Fitzpatrick, Canada
  • Laura Sarantaus, Department of Biological and Environmental Sciences, Genetics, University of Helsinki, Helsinki, Finland., Finland
  • Ingrid Ambus, Genetics Program, North York General Hospital, Toronto, Ontario, Canada, Canada
  • Anne-Marie Gerdes, Clinical Genetics Department of KKA, Odense University Hospital, Odense C, Denmark, Denmark
  • Elisabeth Mangold, Institute of Human Genetics, University of Bonn, Germany, Germany
  • Henry Lynch, Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska, United States
  • Minna Nystrom, Department of Biological and Environmental Sciences, Genetics, University of Helsinki, Helsinki, Finland., Finland

    • A majority of families with hereditary nonpolyposis colorectal cancer (HNPCC) are attributable to germline mutations in DNA mismatch repair (MMR) genes. However, the clinical phenotype of HNPCC patients 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 sebaceous gland neoplasms and visceral malignancies. This is known as Muir-Torre syndrome (MTS), and regarded as a phenotypic variant of HNPCC. Skin neoplasms in MTS have been shown to exhibit high microsatellite instability (MSI), a hallmark of HNPCC, supporting the assumption of shared molecular background of the two syndromes.
    The sebaceous tumors associated with MTS appear in many patients before visceral malignancies, providing important predictability of HNPCC-related cancers in mutation carriers. Since most sebaceous tumors are, however, sporadic, molecular assessment needs to be carried out to verify the presence of the syndrome. Contribution of non-truncating mutations found in skin cancer patients is difficult to interpret and therefore, 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. We assessed their capability to correct DNA mispairs with an in vitro mismatch repair assay. Both mutations were deficient in the assay, which together with tumor findings, high MSI and loss of MSH2 protein expression, suggested their predisposing role in both internal and skin malignancies in the families.
    The functional testing of the two missense mutations in MSH2 supports the notion that Muir-Torre subphenotype of HNPCC is associated with severe functional defects in the repair capability of the mutated proteins, which is compatible with a phenotype fulfilling the Amsterdam criteria in the families.

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