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

• Published in: Nature Communications
• Main Authors: Haraldsdottir, Sigurdis, Rafnar, Thorunn, Frankel, Wendy L, Einarsdottir, Sylvia, Sigurdsson, Asgeir, Hampel, Heather, Snaebjornsson, Petur, Masson, Gisli, Weng, Daniel, Arngrimsson, Reynir, Kehr, Birte, Yilmaz, Ahmet, Haraldsson, Stefan, Sulem, Patrick, Stefansson, Tryggvi, Shields, Peter G, Sigurdsson, Fridbjorn, Bekaii-Saab, Tanios, Moller, Pall H, Steinarsdottir, Margret, Alexiusdottir, Kristin, Hitchins, Megan, Pritchard, Colin C, de la Chapelle, Albert, Jonasson, Jon G, Goldberg, Richard M, Stefansson, Kari
• Other Authors: 1 Department of Internal Medicine, Stanford Cancer Center, 875 Blake Wilbur Drive, Stanford, California 94305-5826, USA. 2 Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, 460West 10th Avenue Columbus, Ohio 43210, USA. 3 University of Iceland, Sæmundargata 2, 101 Reykjavík, Iceland. 4 deCODE genetics/Amgen, Sturlugata 8, 101 Reykjavik, Iceland. 5 Department of Pathology, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue Columbus, Ohio 43210, USA. 6 Landspitali University Hospital, Hringbraut, 101 Reykjavik, Iceland. 7 Aalborg Universitets hospital, 9000 Aalborg, Denmark. 8 Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI/AVL), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. 9 Hvidovre Hospital, Kettegård Allé 30, 2650 Hvidovre, Denmark. 10 Mayo Clinic, Department of Internal Medicine, 5881, E Mayo Blvd, Phoenix, Arizona 85054, USA. 11 Icelandic Cancer Registry, Skogarhlíð 8, 105 Reykjavík, Iceland. 12 University of Washington, 1959 NE Pacific Street, Seattle, Washington 98195, USA. 13 West Virginia University Cancer Institute, Department of Internal Medicine, 1805 Health Sciences Center South Morgantown, 1959 NE Pacific Street, West Virginia 26506, USA.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Nature Publishing Group 2017
• Subjects: Ristilkrabbamein; Ísland; MAO12; MAB12; PTT12; NAF12; SAM12; Lynch Syndrome II; Colorectal Neoplasms; Hereditary Nonpolyposis; Iceland; Lynch; Weaver
• Online Access: http://hdl.handle.net/2336/620229; https://doi.org/10.1038/ncomms14755

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files 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. Ohio State University (OSU) Comprehensive Cancer Center OSU Colorectal Cancer Research fund Obrine-Weaver Fund Pelotonia Fellowship Award deCODE genetics