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Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population

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Abstract

An increasing number of mismatch-repair (MMR) gene mutations have been identified in hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. This study presents the population-based Danish MMR gene mutation profile, which contains 138 different MMR gene alterations. Among these, 88 mutations in 164 families are considered pathogenic and an additional 50 variants from 76 families are considered to represent variants of unknown pathogenicity. The different MMR genes contribute to 40% (MSH2), 29% (MLH1), and 22% (MSH6) of the mutations and the Danish population thus shows a considerably higher frequency of MSH6 mutations than previously described. Although 69/88 (78%) pathogenic mutations were present in a single family, previously recognized recurrent/founder mutations were causative in 75/137 (55%) MLH1/MSH2 mutant families. In addition, the Danish MLH1 founder mutation c.1667+2_1667_+8TAAATCAdelinsATTT was identified in 14/58 (24%) MLH1 mutant families. The Danish Lynch syndrome population thus demonstrates that MSH6 mutations and recurrent/founder mutations have a larger contribution than previously recognized, which implies that the MSH6 gene should be included in routine diagnostics and suggests that directed analysis of recurrent/founder mutations may be feasible e.g. in families were diagnostic material is restricted to archival tissue.

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Acknowledgements

Financial support was granted from the Danish Cancer Society and from the Hvidovre University Hospital. We would also like to acknowledge surgeons, pathologists, and geneticists for identifying these families and reporting data to the national HNPCC-register.

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Authors and Affiliations

  1. Clinical Research Centre and HNPCC-Register, Copenhagen University, Hvidovre University Hospital, Kettegård Allé 30, Hvidovre, 2650, Denmark

    Mef Nilbert

  2. Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark

    Friedrik P. Wikman & Torben F. Örntoft

  3. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Thomas V. O. Hansen & Finn C. Nielsen

  4. Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

    Henrik B. Krarup & Henrik Okkels

  5. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark

    Lone Sunde

  6. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark

    Anne-Marie Gerdes

  7. Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark

    Dorthe Cruger

  8. HNPCC-Register, Hvidovre University Hospital, Hvidovre, Denmark

    Susanne Timshel & Inge Bernstein

  9. Department of Cellular and Molecular Medicine, Panum Institute, Copenhagen University, Copenhagen, Denmark

    Marie-Louise Bisgaard

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  1. Mef Nilbert
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Correspondence to Mef Nilbert.

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Nilbert, M., Wikman, F.P., Hansen, T.V.O. et al. Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. Familial Cancer 8, 75–83 (2009). https://doi.org/10.1007/s10689-008-9199-3

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  • DOI: https://doi.org/10.1007/s10689-008-9199-3

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