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Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

Author

Listed:
  • Sigurdis Haraldsdottir

    (Stanford Cancer Center
    The Ohio State University Comprehensive Cancer Center, 460West 10th Avenue Columbus
    University of Iceland)

  • Thorunn Rafnar

    (deCODE genetics/Amgen)

  • Wendy L. Frankel

    (The Ohio State University Comprehensive Cancer Center)

  • Sylvia Einarsdottir

    (Landspitali University Hospital
    Aalborg Universitets hospital, 9000 Aalborg)

  • Asgeir Sigurdsson

    (deCODE genetics/Amgen)

  • Heather Hampel

    (The Ohio State University Comprehensive Cancer Center, 460West 10th Avenue Columbus)

  • Petur Snaebjornsson

    (Netherlands Cancer Institute—Antoni van Leeuwenhoek (NKI/AVL))

  • Gisli Masson

    (deCODE genetics/Amgen)

  • Daniel Weng

    (The Ohio State University Comprehensive Cancer Center, 460West 10th Avenue Columbus)

  • Reynir Arngrimsson

    (University of Iceland
    Landspitali University Hospital)

  • Birte Kehr

    (deCODE genetics/Amgen)

  • Ahmet Yilmaz

    (The Ohio State University Comprehensive Cancer Center, 460West 10th Avenue Columbus)

  • Stefan Haraldsson

    (Landspitali University Hospital
    Hvidovre Hospital)

  • Patrick Sulem

    (deCODE genetics/Amgen)

  • Tryggvi Stefansson

    (Landspitali University Hospital)

  • Peter G. Shields

    (The Ohio State University Comprehensive Cancer Center, 460West 10th Avenue Columbus)

  • Fridbjorn Sigurdsson

    (Landspitali University Hospital)

  • Tanios Bekaii-Saab

    (Mayo Clinic)

  • Pall H. Moller

    (Landspitali University Hospital)

  • Margret Steinarsdottir

    (Landspitali University Hospital)

  • Kristin Alexiusdottir

    (Icelandic Cancer Registry)

  • Megan Hitchins

    (Stanford Cancer Center)

  • Colin C. Pritchard

    (University of Washington)

  • Albert de la Chapelle

    (The Ohio State University Comprehensive Cancer Center, 460West 10th Avenue Columbus)

  • Jon G. Jonasson

    (University of Iceland
    Landspitali University Hospital
    Icelandic Cancer Registry)

  • Richard M. Goldberg

    (West Virginia University Cancer Institute, 1805 Health Sciences Center South Morgantown)

  • Kari Stefansson

    (University of Iceland
    deCODE genetics/Amgen)

Abstract

Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

Suggested Citation

  • Sigurdis Haraldsdottir & Thorunn Rafnar & Wendy L. Frankel & Sylvia Einarsdottir & Asgeir Sigurdsson & Heather Hampel & Petur Snaebjornsson & Gisli Masson & Daniel Weng & Reynir Arngrimsson & Birte Ke, 2017. "Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14755
    DOI: 10.1038/ncomms14755
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