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

Sigurdis Haraldsdottir (), Thorunn Rafnar, Wendy L. Frankel, Sylvia Einarsdottir, Asgeir Sigurdsson, Heather Hampel, Petur Snaebjornsson, Gisli Masson, Daniel Weng, Reynir Arngrimsson, Birte Kehr, Ahmet Yilmaz, Stefan Haraldsson, Patrick Sulem, Tryggvi Stefansson, Peter G. Shields, Fridbjorn Sigurdsson, Tanios Bekaii-Saab, Pall H. Moller, Margret Steinarsdottir, Kristin Alexiusdottir, Megan Hitchins, Colin C. Pritchard, Albert de la Chapelle, Jon G. Jonasson, Richard M. Goldberg and Kari Stefansson ()
Additional contact information
Sigurdis Haraldsdottir: Stanford Cancer Center
Thorunn Rafnar: deCODE genetics/Amgen
Wendy L. Frankel: The Ohio State University Comprehensive Cancer Center
Sylvia Einarsdottir: Landspitali University Hospital
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
Birte Kehr: deCODE genetics/Amgen
Ahmet Yilmaz: The Ohio State University Comprehensive Cancer Center, 460West 10th Avenue Columbus
Stefan Haraldsson: Landspitali University 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
Richard M. Goldberg: West Virginia University Cancer Institute, 1805 Health Sciences Center South Morgantown
Kari Stefansson: University of Iceland

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14755

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